Next Article in Journal
Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut
Previous Article in Journal
Glycosylation of Cancer Extracellular Vesicles: Capture Strategies, Functional Roles and Potential Clinical Applications
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 10
Issue 1
10.3390/cells10010110
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

microRNAs Mediated Regulation of the Ribosomal Proteins and its Consequences on the Global Translation of Proteins

by
Abu Musa Md Talimur Reza
1,2 and
Yu-Guo Yuan
1,3,*
1
Jiangsu Co-Innovation Center of Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
2
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland
3
Jiangsu Key Laboratory of Zoonosis/Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China
*
Author to whom correspondence should be addressed.
Cells 2021, 10(1), 110; https://doi.org/10.3390/cells10010110
Submission received: 22 November 2020 / Accepted: 14 December 2020 / Published: 8 January 2021
Browse Figures
Versions Notes

Abstract

:
Ribosomal proteins (RPs) are mostly derived from the energy-consuming enzyme families such as ATP-dependent RNA helicases, AAA-ATPases, GTPases and kinases, and are important structural components of the ribosome, which is a supramolecular ribonucleoprotein complex, composed of Ribosomal RNA (rRNA) and RPs, coordinates the translation and synthesis of proteins with the help of transfer RNA (tRNA) and other factors. Not all RPs are indispensable; in other words, the ribosome could be functional and could continue the translation of proteins instead of lacking in some of the RPs. However, the lack of many RPs could result in severe defects in the biogenesis of ribosomes, which could directly influence the overall translation processes and global expression of the proteins leading to the emergence of different diseases including cancer. While microRNAs (miRNAs) are small non-coding RNAs and one of the potent regulators of the post-transcriptional gene expression, miRNAs regulate gene expression by targeting the 3′ untranslated region and/or coding region of the messenger RNAs (mRNAs), and by interacting with the 5′ untranslated region, and eventually finetune the expression of approximately one-third of all mammalian genes. Herein, we highlighted the significance of miRNAs mediated regulation of RPs coding mRNAs in the global protein translation.

Graphical Abstract

1. Introduction

MicroRNAs (miRNAs) and Ribosomal proteins (RPs) are two important classes of regulatory molecules that control the translation of proteins from messenger RNA (mRNA). RPs are highly conserved proteins across all the forms of life [1], at least 53 RPs are detected in Escherichia coli and 80 RPs are detected in mammals [2], which are active structural components of ribosomes, the machinery and master regulators of the protein translation process. Deregulation of RPs could interfere with the overall translation process by generating ribosome heterogeneity (‘specialized ribosomes’), which may change the global protein synthesis and/or favor the translation of a subset of proteins [3,4,5]. While miRNAs is a class of non-coding RNAs that can interfere with the protein translation process by targeting the 3′-untranslated region and/or coding region of mRNAs [6] as well as interacting with the 5′ untranslated region [7] and eventually the expression of approximately one-third of all mammalian genes, which are finetuned by the miRNAs [8]. Similarly, the expressions of RPs are also finetuned by the miRNAs binding to their transcripts following the facilitation or restriction of the translation process [7,9,10,11]. The miRNAs involved in the regulation of RPs coding mRNAs are eventually regulating the global translation of proteins through its subsequent impact on the biogenesis of ribosomes as well as the assembly and formation of the translation machinery [7]. Therefore, understanding this group of miRNAs required extra attention and will improve our understanding of the multi-dimensional interactions among miRNAs, RPs, biogenesis of ribosomes and global gene expressions.
Several excellent reviews have focused on the biogenesis of miRNAs [12,13,14,15] and their regulatory roles on the overall process of translation [10,11,16,17,18]. Those reviews are excellent resources in order to develop an understanding of the regulatory roles of miRNAs in gene expression. However, the understanding of miRNAs mediated regulation of RPs coding mRNAs is still in the primary stage, and literally very few original researches have been published in this context. Therefore, an overview outlining the potential and importance of investigating the regulatory role of miRNAs on the Ribosomal protein coding mRNAs is required. Herein, we summarize the interaction and networking among the miRNAs, RPs, ribosome biogenesis and global gene expression, and their direct and indirect influence on the disease progression. Firstly, we discuss the regulatory roles of RPs on the biogenesis of ribosomes, assembly and formation of translation machinery, translation of the proteins and the progression of diseases. Secondly, we discuss the regulatory roles of miRNAs on the translation and expression of the RPs, and the interaction and networking between miRNAs and RPs. Finally, we discuss the cumulative and interactive influence of the miRNAs and RPs on disease progression and provide conclusive remarks to conduct future research on this topic.

2. Materials and Methods

Published related articles were searched for using keywords: Ribosomal proteins (RPs), miRNAs, gene expression, translation, post-transcriptional regulation of mRNA and ribosomopathy in the National Center for Biotechnology Information PubMed database up until November 2020. Relevant articles published in English were included in this review. We only focused on the RPs and the diseases related to the deregulation of RPs, and the miRNAs targeting RPs. Human RPs were categorized according to their involvement in different biological processes using the DAVID bioinformatics resources (https://david.ncifcrf.gov/). The genetic alteration status of the 73 RPs coding genes, and its consequences in different types of cancer patients were analyzed using the cBioPortal for Cancer Genomics (http://www.cbioportal.org/index.do) database from the cancer genome atlas (TCGA) Research Network (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga). For analysis, all samples (10,967 samples) in “TCGA PanCancer Atlas Studies (32 categories)” were included and analyzed as a group for checking the genetic alteration (both mutation and copy number alteration) and overall survival status of the patients, the bookmark link of the analysis is collected for future reference or revisit (http://bit.ly/2YsULwu). The expression pattern of 73 RPs coding mRNA (heatmap) in “serous ovarian cancer (TCGA PanCancer Atlas)” samples was also generated from the cBioPortal database, and the bookmark link was collected for future reference or revisit (http://bit.ly/2Lxitmg), in which 300 clinical ovarian cancer patients samples having mRNA expression data (RNA Seq V2) were taken into consideration. The interaction between RPs and miRNAs was predicted using miRNet database (https://www.mirnet.ca/), which is an integrated platform to link the miRNAs to their target mRNAs and their functions.

3. RPs on the Biogenesis and Assembly of Ribosomes, and Translation of Proteins

A ribosome is a supramolecular ribonucleoprotein complex [19], composed of Ribosomal RNA (rRNA) and RPs, and coordinates the translation and synthesis of proteins with the help of transfer RNA (tRNA) and other factors [19]. Increase or decrease in the biogenesis of ribosomes directly influence the translation process and global gene expression following the growth, proliferation and differentiation of the cells [19,20,21,22], as well as physiological processes and progression of diseases [20,23,24,25]. RPs are mostly derived from the energy-consuming enzyme families such as ATP-dependent RNA helicases, AAA-ATPases, GTPases and kinases [26] and are involved in a vast array of biological processes (Table 1). Although RPs are known for their inevitable role in the biogenesis and assembly of translation machinery (Table 2), not all RPs are indispensable for functional ribosomes. The ribosome complex could be functional and continue the translation of proteins instead of lacking in some RPs [27], but the efficacy and accuracy of protein synthesis might be compromised. For example, Ribosomal protein L33 (RPL33) is required for ribosome biogenesis, subunit joining, and a mutation in RPL33 causes the repression of GCN4 translation in yeast [28], which is a transcription factor and master regulator of the genes, and is highly conserved in mammalian species named as activating transcription factor-4 (ATF4) [29]. The mutation in RPL33 also reduces the processing efficiency of the 35S and 27S pre-rRNAs following the reduction of the accumulation of all four mature rRNAs [28]; thus, RPL33 could have a mass influence on the global gene expression through the deregulation of master transcription factor GCN4 or ATF4. Similarly, Ribosomal protein S20 (RPS20) is responsible for the mRNA binding and subunits association, and lacking RPS20 causes drastic reduction in the formation of the 70S complex as well as mRNA binding through an initiation that defects to the 30S subunit [30]. Ribosomal protein L16 (RPL16) is required for the assembly of 60S subunits, and Ribosomal protein 59 (RP59) is required for the assembly of the 40S subunit [31], while Ribosomal protein L1 (RPL1) plays essential roles in maintaining the stability of 5S rRNA as well as the assembly of 60S subunits in yeast [32,33] and Ribosomal protein L9 (RPL9) is essential for the small subunit maturation in E. coli bacteria [34]. Therefore, many of the RPs are eventually essential for the proper biogenesis, assembly and functioning of the translation machinery.
In addition to the assembly of ribosomes, RPs play important accessory roles to facilitate the biosynthesis and post-translational modification of proteins such as processing and folding of rRNA, assembly and transportation of the precursors of ribosomes, stabilization of the Ribosomal subunits [35], enzymatic activities [36], as well as folding [37,38] and co-translational translocation [39,40] of the proteins. Take, for example, the Ribosomal protein L23 (RPL23), which is a docking site for a chaperone on the ribosome, and has a regulatory role on the chaperone-assisted folding of proteins [37], RPL23a along with Ribosomal protein L35 (RPL35) also showed an important role during peptide recognition and insertion to the translocation channel by repositioning SRP54 [38]. Similarly, Ribosomal protein S12 (RPS12), Ribosomal protein S4 (RPS4), Ribosomal protein S9 (RPS9) and Ribosomal protein S28 (RPS28) are important for translational accuracy [41,42,43,44], while Ribosomal protein L3 (RPL3), Ribosomal protein L5 (RPL5), Ribosomal protein L24 (RPL24), Ribosomal protein L39 (RPL39) and Ribosomal protein L41 (RPL41) potentially influence the peptidyltransferase activity and subunit association of the ribosomes [45,46,47]. Furthermore, RPL5 regulates the anchoring of the peptidyl-tRNA to the P-site in Yeast [47], and Ribosomal protein L10 (RPL10) plays an important role in the nuclear export by interacting and releasing cytoplasmic Nmd3p from the 60S subunit [48,49,50]. The interaction between Ribosomal protein L1 (RPL1) and Ribosomal protein L16 (RPL16) is required for the stabilization of 5S rRNA, while Ribosomal protein L12 (RPL12) mediates the correct assembly of ribosomal stalk [32,33,51,52]. Ribosomal protein S14 (RPS14), Ribosomal protein S0 (RPS0) and Ribosomal protein S21 (RPS21) are involved in the cytoplasmic rRNA processing steps leading to the maturation of 18S rRNA [53,54,55]. Ribosomal protein L25 (RPL25) is required for pre-rRNA processing [56]. The Ribosomal protein S15 (RPS15) is required for a nuclear exit of the 40S subunit precursors in yeast [57] and Ribosomal protein S14 (RPS14) is required for the maturation of 43S pre-ribosomes [53]. Ribosomal protein S12 (RPS12) increases the rate of translation with the cost of high rate of error in the protein synthesis, while Ribosomal protein S4 (RPS4) and Ribosomal protein S5 (RPS5) are required to maintain the accuracy of protein translation [58,59,60]. Therefore, RPs are an integral part of the translation machinery, and many of them play an inevitable role during the biogenesis of ribosomes and the translation process, while few of them might be dispensable for a functioning translation machinery but must have its consequences.

4. RPs Mediated Regulation of Biological Processes and Progression of Diseases

RPs are not simply static building blocks of the ribosome; they are critical regulators of different biological processes (Table 1), important components of cellular organelles (Supplementary Table S1) and are involved in various molecular functions (Supplementary Table S2) of the cells. RPs are directly and indirectly involved in the various important molecular signaling pathways such as RP-MDM2-p53 signaling [62,63], which are involved in the regulation of diverse physiological processes including energy metabolism to the growth and proliferation of the cells. Hence, deregulation of RPs impairs the synthesis, processing and assembly of rRNA, translation and modification of proteins, and eventually lead to the progression of diseases (Table 3) including developmental, systemic and metabolic complications, and cancers [24,62,63,64,65,66]. The diseases that are derived from the structural and functional defects of the RPs or rRNA genes or the genes in which products are involved in the assembly and biogenesis of ribosomes are defined by the term ribosomopathy [67,68,69]. The diseases that come under the term ribosomopathy include Diamond-Blackfan anemia (DBA), 5q-syndrome, Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DC), cartilage hair hypoplasia (CHH), Treacher Collins syndrome (TCS), Bowen-Conradi syndrome (BCS), North American Indian childhood cirrhosis (NAIC) [67].
DBA is characterized by anemia, retardation of growth and congenital deformities, and could be a result of the structural and functional defects of 10–15 ribosomal proteins including RPS19, RPS26, RPL5 and RPL11 [70,71,72]. 5q-syndrome is a type of anemia that is caused by the haplo-insufficiency of RPS14 [73], a critical component for 40S assembly, and depletion of RPS14 in human CD34+ cells is sufficient to recapitulate the 5q-defect of erythropoiesis with sparing of megakaryocytes [91]. The clinical sign of SDS disease includes exocrine pancreatic insufficiency, hematologic abnormalities such as neutropenia, neurocognitive dysfunction [92,93,94], and results from the bi-allelic mutations in the ribosome maturation protein SBDS, which compromises its ability to couple GTP hydrolysis by the GTPase EFL1 to the release of eIF6 from the 60S subunit [74]. DC is the X-linked subtype of dyskeratosis congenita, and the symptoms include mucocutaneous abnormalities such as pigmented skin, changes of nail, failure of bone marrow and pulmonary fibrosis [75]. CHH is characterized by the short stature deformities of bone and abnormalities in the growth of hair and potentially results from mutation of the RMRP gene [76]. TCS is identified by the craniofacial abnormalities and caused by the mutation in the TCOF1 gene [77], which is involved in rRNA transcription. BCS is the result of an autosomal recessive abnormality of the EMG1 gene, which plays a role in small ribosomal subunit assembly [78,79,80]. NAIC is an autosomal recessive abnormality of the CIRH1A gene, which codes for cirhin, and clinical symptoms include biliary, cirrhosis, portal and hypertension [81,82].
The clinical patient data obtained from the cBioportal database (https://www.cbioportal.org/) of the TCGA research network showed the frequent copy number alteration of the RPs coding genes (Figure 1a). It also showed that the patients with an alteration status of RPs had lower median month survival compared to the patients without alterations in the RPs (Figure 1b). Moreover, deregulated expression of the RPs is also recorded at the mRNA level, for example, the RNA-seq data of 300 ovarian cancer patients obtained from the same database (Supplementary Figure S1). The deregulated expression of the RPs in different types of cancers is also supported by the published research findings [95,96,97,98], such as breast cancer [99,100], gastric cancer [101], hepatocellular cancer [102], colorectal cancer [103,104,105], prostate cancer [66,106], and the expression of RPs varies between normal and malignant cells as well as across the types of cancers [107]. For example, downregulation of Ribosomal protein S6 (RPS6) inhibits the growth of non-small cell lung cancer by inducing cell cycle arrest, rather than apoptosis [83], X-linked ribosomal protein S4 (RPS4X) is an independent prognostic factor in patients with serous epithelial ovarian cancer, and the low expression of RPS4X is associated with a poor prognosis in human serous epithelial ovarian cancer [85] and bladder cancer [86], RPL31 is overexpressed in prostate carcinomas compared with benign prostate tissues, and Ribosomal protein L31 (RPL31) might promote the growth of prostate cancer cell by increasing the degradation of tumor suppressor p53 [87]. Ribosomal Protein L34 (RPL34) functions as an oncogene and modulates esophageal cancer cells by the inactivation of the PI3K/Akt signaling pathway, and silencing of RPL34 inhibits the proliferation and metastasis of esophageal cancer cells [88]. Ribosomal Protein L22 (RPL22) controls the dissemination of T-cell lymphoma: single copy loss of RPL22 promoted lymphomagenesis and dissemination, while loss of both copies results in mediastinal retention [89]. Mutation of Ribosomal Protein S20 (RPS20) in the germline cells might cause hereditary nonpolyposis colorectal carcinoma [90]. Based on the above discussion, the RPs are not only the building block of the translation machinery, but also have important roles in other physiological processes, and deregulation of the RPs might cause severe diseases including different types of ribosomopathy and cancers.

5. MicroRNAs Mediated Regulation of Gene Expression and Progression of Diseases

miRNAs are small non-coding RNAs (~22 nucleotides in length) and are involved in RNA silencing [14]. miRNAs are one of the potent regulators of the post-transcriptional gene expression, which regulate gene expression by targeting the 3′ untranslated region and/or coding region of the mRNAs [6], and also by interacting with the 5′ untranslated region [7], and eventually finetune the expression of approximately one-third of all mammalian genes [8]. These findings have established the fact that miRNAs are an inevitable mediator of health and diseases in both humans and animals [108,109]. Many publications reported the involvement of miRNAs in almost all bio-physiological processes starting from the germ cells [109] to the development of the nervous system [110], immune regulation [111,112,113], and proliferation and differentiation of cells [114,115,116,117,118]. As well, miRNAs are reported to be involved in numerous human and animal diseases: for example, miRNAs are detected as both oncomir and tumor suppressors, and their roles varied depending on the miRNA-family as well as the type of cancer [119,120,121,122,123,124,125,126]. However, there is a prominent trend of global suppression of miRNAs expression in different types of cancers [127], and this process of global suppression of miRNAs expression could be a result of multiple conditions such as genomic defects in the miRNA coding region (mutations, amplifications or deletions), transcription factor mediated repression (such as Myc), epigenetic alterations in the promoter region (CpG islands hypermethylation), and the deregulation of Dicer and Drosha, the machineries for the processing of miRNAs [127].
Deregulated expression of miRNAs is detected with many other types of diseases such as neurodegenerative diseases including Alzheimer’s, Parkinson’s, Huntington’s disease [128,129] and amyotrophic lateral sclerosis [130], eye diseases including glaucoma, and myopia [129,131], traumatic brain injury [132], diabetes [133], rheumatoid arthritis [134,135], autoimmune and chronic inflammatory diseases [136], lung diseases [137], skeletal diseases [138], age-related diseases [139,140], myocardial infarction and cardiovascular diseases [141,142]. In addition, certain physiological abnormalities, such as hypoxia, which is a reduction in the normal tension of tissues oxygen (O2) level, and a characteristics feature of chronic vascular and pulmonary disease and many cancers, resulted in a deregulated expression of miRNAs [143], and several hypoxia induced miRNAs play important roles in the adaptation of cancer cells to the hypoxia [143]. miRNAs are also involved in the immune suppression process and the potential use of miRNAs manipulation strategy for prolonging the immune tolerance following the survival of allograft is also evident through preclinical studies [144]. Therefore, proper understanding of miRNAs related regulation of health and diseases will clarify the ways to develop treatment strategies and preventive measures against many fatal diseases.

6. MicroRNAs Biogenesis and Dissemination to the Circulatory System

By regulating, finetuning and silencing of the protein-coding transcripts, miRNAs play an inevitable role in gene expression, molecular signaling and pathological conditions of different diseases. There are excellent reviews that explain every aspect of miRNAs biogenesis [12,13,14,15]. However, the dissemination of miRNAs to the circulatory system and its role in the cell–cell and cell–stromal crosstalk need to be explained here for a proper understanding of the discussed topic in this review. As shown in Figure 2a, cells (under both normal and diseased conditions) produce different kinds of extracellular vesicles including the exosomes [120], microvesicles [145] and exophers [146], which are used to expel the waste material outside of the cells. These extracellular vesicles contain protein, miRNAs, lipids and other waste material derived from the originating cells. Therefore, these vesicles are excellent biomarkers to study the pathological conditions of the originating cells. In addition to dumping the waste materials of the cells, these vesicles containing the proteins and miRNAs from the originating cells could be carried by the circulatory system to the neighboring cells as well as to the distant tissues, and thereby participate in the cell–stromal and cell–cell communication. Therefore, the miRNAs do not only influence the gene expression of its mother cells, but it can also influence the gene expression and transcript silencing of the neighboring cells and distant tissues. This signifies the role of miRNAs in the progression and dissemination of diseases to the secondary organs, which means organs other than the organ of the disease outbreak.

7. MicroRNAs in the Regulation of Ribosomal Protein Coding mRNAs

miRNAs are involved in the regulation and finetuning of at least one third of all mammalian genes [8], and thus, it is not unusual to anticipate that miRNAs are also interfering with the post-transcriptional expressions of most of the ribosomal proteins coding mRNAs and eventually finetuning the overall protein synthesis. To illustrate, firstly, the deregulation in the expression of miRNAs, which are involved in the regulation of RPs coding mRNAs, could result in an imbalanced synthesis of RPs. Secondly, an imbalance in the expression of RPs could lead to the defective assembly and biogenesis of the ribosomes, and/or functional abnormality to the translation machinery [19,20,21,22]. Finally, the structural and functional abnormality of the ribosomes results in an inefficient and atypical translation, and eventually influences the global translation of proteins (Figure 2b) followed by the physiological abnormalities and progression of diseases [20,23,24,25]. Take, for example, miR-10a, which is reported to positively influence the global translation of proteins by interacting with the 5′ untranslated region of the ribosomal protein coding mRNAs [7]. This signifies that the RPs regulatory miRNAs could be considered as master miRNAs, which might be a small group but potentially interferes with the global expression of the genes. Therefore, understanding this group of miRNAs required extra attention, and will improve our understanding of the multi-dimensional interactions among miRNAs, RPs, biogenesis of ribosomes and global gene expressions. However, the investigation about the role of miRNAs on the RPs are very limited, the very few findings in this field includes: miR-7641 potentially play a role in cancers through the regulation of ribosomal protein S16 (RPS16) [9], miR-10a positively influences the global translation of proteins by interacting with the 5′ untranslated region of the ribosomal protein coding mRNAs [7], and miR-147b inhibits the proliferation and invasiveness of the non-small cell lung cancer (NSCLC) by downregulating the RPS15A mediated signaling of the Wnt/β-catenin [84].
Now, two things are very clear: (1) there are master miRNAs that can influence the global translation of proteins [7], and (2) the number of investigations is very small to understand miRNAs mediated regulation of RPs. However, a vast network between the RPs and miRNAs is predicted by the in-silico analysis (Supplementary Figure S2), which shows more than a thousand miRNAs are potentially involved in the regulation of RPs. To find out the most vulnerable RPs to the miRNAs attack, the top 15 RPs were sorted based on their number of connections to the miRNAs, which include RPL41, RPL14, RPL18A, RPS15A, RPL13A, RPL24, RPS24, RPL37, RPS16, RPL12, RPS27A, RPS19, RPL27A, RPL23A, and RPLP0, respectively (Figure 3a); these 15 RPs are predicted to be connected with around 800 miRNAs (Supplementary Table S3). On the other hand, to distinguish the most important miRNAs, the top 14 miRNAs were grouped based on their number of connections with the RPs, these include hsa-mir-16-5p, hsa-mir-92a-3p, hsa-mir-100-5p, hsa-mir-615-3p, hsa-mir-484, hsa-mir-186-5p, hsa-mir-320a, hsa-mir-193b-3p, hsa-let-7a-5p, hsa-mir-331-3p, hsa-mir-92b-3p, hsa-mir-652-3p, hsa-mir-766-3p, and hsa-mir-744-5p, respectively (Figure 3b). These 14 miRNAs are potentially connected with most of the RPs and are reported to be involved in many diseases including different types of cancers (Table 4). A brief review about the above-mentioned 14 miRNAs is performed to understand the already known roles of those miRNAs, in terms of their involvement in the biophysiological processes and progression of diseases.
The top connected miRNA to the RPs is miR-16-5p, which is an important miRNA, plays a role in the proliferation and differentiation of cells [266], and regulates different types of cancers, such as breast cancer cells by targeting VEGFA [147] and restraining the AKT3 mediated NF-κB pathway [148], hepatocellular carcinoma (HCC) by targeting IGF1R [149], mesothelioma by targeting CCND1 and BCL2 [150], glioma by targeting the cell cycle and apoptotic mediators [151], neuroblastoma by targeting MYCN [152], as well as regulates chordoma, gastric cancer and osteoarthritis by targeting SMAD3 [153,154,155] and provides protection against LPS-induced cell injury by targeting CXCR3 [267]. Furthermore, miR-16-5p might have a role in osteoclastogenesis [156] and could be an important biomarker of rheumatoid arthritis [157]. This signifies that miR-16-5p is an active regulator of different biological processes, and further investigation is required, particularly to understand how it influences the expression of RPs, which has not been investigated.
The second top miRNA is mir-92a-3p, which has involvement in several pathological conditions: it is a potential oncomir [158,268], overexpression creates resistance to the TRAIL-dependent apoptosis by suppressing MYCBP2 in melanoma [158], promotes the progression of liposarcoma by stimulating the tumor-associated macrophages to secret IL6, a proinflammatory cytokine [159], promotes tumorigenesis in glioma cells by regulating cadherin 1 (CDH1)/β-catenin signaling but at the same time reduces the stemness of glioma stem cells (GSCs) by modulating Notch-1/Akt signaling [160]. Similarly, blocking of miR-92a-3p induces apoptosis in leukemia [161] and colorectal cancer cells [162,163]. Instead of its pro-cancer role, it prevents the degradation of cartilage by targeting WNT5A [164] and might be therapeutically significant for the treatment of osteoarthritis. It also has diagnostic value, miR-92a-3p is a biomarker for several diseases such as Kawasaki disease [165], schizophrenia [166], systemic lupus erythematosus [167], and white matter impairment and post-stroke depression [168]. However, the involvement of miR-92a-3p in the regulation of RPs is not investigated, which is important to understand its role in the regulation of translation machinery.
The third, fourth and fifth miRNAs in the list are miR-100-5p, miR-615-3p and miR-484, respectively: oncogenic miR-100-5p is a potent regulator of viability, metastasis and apoptosis of different cancer types, blocking of miR-100-5p induces apoptosis and prevents the re-emergence of prostate cancer [169], renal cell carcinoma (RCC) [170], oral cancer [171] and NSCLC [172]. It could also be used as a prognostic marker for HCC [173], abeta-induced pathologies [174] and hidradenitis suppurativa [175]. While, miR-615-3p plays important role in the differentiation of cells, it suppresses GDF5 and FOXO1 and inhibits osteogenesis in the lumbar ligamentum flavum cells [269], it is also known to have a feed-forward loop with HOXC5, and repress hTERT during the differentiation of cells [270]. In cancer, miR-615-3p plays a dual role depending on the type, for example, it promotes gastric cancer potentially by targeting CELF2 [176] and prostate cancer [177], but reported to be a suppressor of NSCLC potentially targeting IGF2 [178,179] and esophageal cancer [180]. In addition, it could be used as a biomarker for the recurrent HCC [181] and also regulates lipoapoptosis by targeting the C/EBP homolog in mice [271]. Similarly, miR-484 plays both ani- and pro-cancer role depending on the types, and it attenuates the epithelial to mesenchymal transition of cervical cancer by targeting ZEB1 and SMAD2 [182], metastasis by targeting MMP14 and HNF1A [183], and is usually downregulated in gastric cancer [184]. However, overexpression of miR-484 is considered as a poor prognosis factor for glioma patients, which targets MAP2 and activates ERK1/2 signaling resulting in the stemness characteristics of glioma cells [185]. miR-484 also promotes NSCLC by targeting APAF-1 [186] and adrenocortical cancer by targeting Fis1 [187], which are regulators of apoptosis. In addition, the presence of miR-484 in the blood serum could be considered as a biomarker for both NSCLC [272] and colorectal cancer [188]. As well, miR-484 promotes neurogenesis by targeting PCDH19 [273], prevents ischemia-reperfusion injury by inhibiting CAS3 and CAS9 mediated apoptosis of myocardial cells in rats [274], creates resistance to sunitinib mediated therapy in metastatic renal carcinoma [189] and reverses cytidine deaminase axis (CDA)-mediated chemoresistance in breast cancer [190].
The sixth and seventh most connected miRNAs to RPs are miR-186-5p and miR-320a, respectively: miR-186-5p is involved in several neurological and cardiac diseases such as the ischemia stroke, hippocampal neurons and coronary syndrome. In ischemia stroke, it targets IGF-1 that causes the apoptosis of neurons [191], while it regulates hippocampal neurons by controlling GLUA2 expression [192]. It prevents glucose-mediated injury of cardiomyocytes [275], potentially by regulating TLR3 [276] and could be a prognosis factor for acute coronary syndrome [193]. Furthermore, miR-186-5p regulates the secretion of FSH indicating its potential role in reproductive health [194]. In cancer, miR-186-5p showed both anti- and pro-cancer roles; for example, it shows anti-tumor properties in osteosarcoma by targeting FOXK1 [195] and TBL1XR1 [196], in colorectal cancer by targeting ZEB1 [197], in NSCLC by targeting SIX1 and in neuroblastoma by downregulating Eg5 [198], while it promotes lung adenocarcinoma by targeting PTEN [199] and metastatic prostate cancer [200]. On the other hand, miR-320a appears to be a global anti-cancer miRNA and reported to inhibit numerous types of cancers such as HCC by regulating HMGB1 expression [201,202], NSCLC by inhibiting the expression of ELF3 and inactivating PI3K/Akt signaling [203], gliomas by targeting SND1 and β-catenin [204], gastric cancer by targeting FOXM1-P27KIP1 [205] and RAB14 [206], lung adenocarcinoma by regulating STAT3 [207], tongue squamous cell carcinoma [208], multiple myeloma by inhibiting PBX3 [209], breast cancer by suppressing Rab14 [210], colorectal cancer by inhibiting RAC1 [211] and bladder carcinoma by directly inhibiting ITGB3 [212]. However, overexpression of miR-320a causes several non-cancer diseases including diabetic nephropathy by downregulating MafB [213], IL-1β-induced cartilage degradation by regulating PBX3 and NF-κB [214], osteoporosis [215] potentially by inhibiting MAP9 and PI3K/AKT signaling [216], doxorubicin-induced cardiotoxicity by targeting VEGF [217], anomalous placentation by targeting ERRγ [218], and atherogenesis by inhibiting SRF [219]. In addition, miR-320a could be a diagnostic tool for arrhythmogenic cardiomyopathy [220] and polycystic ovary syndrome [221].
The eighth, ninth and tenth of the candidate miRNAs are miR-193b-3p, let-7a-5p and miR-331-3p, respectively. Regulation of chondrogenesis by miR-193b-3p, potentially by the regulation of HDAC3, MMP19 and MMP16 is well documented [277,278,279]. It also contributes to preeclampsia by binding to the 3′UTR of TGFβ [222] and plays an anti-cancer role in several cancers, namely ovarian cancer by targeting PAK3 [223], breast cancer by regulating MORC4 [224], and urothelial cancer by targeting ETS1 and Cyclin D1 [225]. While, let-7a-5p inhibits osteogenesis and several cancers, the osteogenesis is inhibited by targeting TGFBR1 [226], and the lung cancer is inhibited by mediating G1/S phase arrest [227] most probably by regulating BCL2L1-mediated PI3Kγ signaling [228], it also inhibits HCC [229]. In addition, it could be a diagnostic marker for metastatic colorectal cancer [230] and might play an anti-apoptotic role in leukemia cells [231]. Among non-cancer diseases, let-7a-5p is involved in the pathogenesis of diabetic nephropathy by targeting HMGA2 [232], and could be a marker for hepatic fibrosis [233]. Similarly, miR-331-3p is also involved in different disease conditions, and known for both anti- and pro-oncogenic characteristics in different types of cancers: it promotes pancreatic cancer by targeting ST7L [234], HCC by downregulating E2F1 [235] and ING5 [236], while its’ presence in the serum indicates the invasive status of the HCC [237] as well as recurrence in the case of esophageal adenocarcinoma [238]. On the other hand, miR-331-3p is reported to play an anti-cancer role in prostate cancer by targeting the RALA pathway [239] and ERBB-2 mediated androgen receptor signaling [240], colorectal cancer by targeting HER2 [241], NSCLC by targeting ErbB2, VAV2 and inhibiting epithelial to mesenchymal transition [242], glioblastoma and cervical cancer by regulating NRP-2 [243,244], ovarian cancer by targeting RCC2 [245], urothelial cancer by targeting NACC1 [246], and gastric cancer by targeting E2F1 [247]. miR-331-3p also plays a role in inhibiting intracranial aneurysm by regulating TNF-α and CD14, as well as by maintaining contractile vascular smooth muscle [248].
The remaining of the 14 most important RPs regulating miRNAs are miR-92b-3p, miR-652-3p, miR-766-3p and miR-744-5p, respectively. Interestingly, miR-92b-3p acts as a preventive molecule against several neural and cardiac diseases [280]; for example, it facilitates the growth of neurite, and healing of acute spinal cord injury by mediating the PTEN/AKT pathway [249]. Another example is cardiac hypertrophy, which is suppressed in mice by miR-92b-3p, potentially by targeting MEF2D [250] and HAND2 [251]. Furthermore, it can inhibit the pulmonary artery derived smooth muscle cells proliferation by targeting USP28 [281], as well as regulate the assembly of primordial follicles in the ovaries of neonatal mice by targeting TSC1 [282]. In cancer, miR-92b-3p have both anti- and pro-cancer roles in different types of cancers: it suppresses pancreatic cancer by targeting GABRA3 [252], but promotes several others such as colorectal cancer by inhibiting FBXW7 [253], esophageal squamous cell carcinoma by target KLF4 and DCS2 [254], gastric cancer by downregulating MMP2, MMP9 and HOXD10 [255], and also could be a biomarker for synovial sarcoma [256]. Similarly, miR-652-3p is also reported to have both anti- and pro-cancer characteristics, it sensitizes lymphoblastic leukemia cells to chemotherapy [257] but promotes bladder cancer by targeting KCNN3 [258], NSCLC by targeting Lgl1 [259] as well as prostate cancer [260]. In addition, miR-652-3p inhibits healing of endothelial damage and atherosclerosis by downregulating Cyclin D2 [261] but promotes trophoblast cells proliferation potentially by targeting HOXA9 and regulating EphB4 [283]. miR-766-3p is also known as a dual player in cancer, it showed an anti-cancer effect on HCC by targeting WNT3A [262], but it is also known to inhibit cell-cycle progression and metastasis of RCC by targeting SF2 [263] and HCC by targeting MTA3 [284], respectively. Furthermore, it plays roles in anti-inflammatory signaling by indirectly inhibiting NF-κB signaling [285]. However, miR-744-5p is reported by only two publications and both claimed its inhibitory role in cancer, which includes ovarian cancer cells by targeting HNRNPC and NFIX [264] and NSCLC by targeting PAX2 [265]. Taken together, the 14 most important miRNAs based on their connection to the RPs (Figure 3b and Table 4) are well involved in different diseases, particularly in different types of cancers. However, their role in the regulation of RPs coding mRNAs is not really investigated, which is very important for understanding the impact of miRNAs on the functioning of translation machinery as well as the global synthesis of proteins.

8. Conclusions

I.
The role of miRNAs in the regulation of gene expression is a well-investigated area of research, however, the roles of miRNAs in the regulation of RPs coding gene expression remains unexplored, and therefore, this area is required to be investigated further for a proper understanding of RPs synthesis, ribosomal assembly and regulation of global protein translation.
II.
The idea of master miRNAs that can influence the global translation of proteins is potentially true, and the existence of such miRNAs is further assured by the report of Orom et al. 2008, which showed that miR-10a binds to the 5′UTR of the RPs and regulates the global protein synthesis. However, further investigations are required to establish it as a scientific fact.
III.
RPs are an integral part of the translation machinery, required for the proper assembly and functioning of the ribosomes. Therefore, the ultimate results of the miRNA mediated regulation of the RPs are improper functioning of the translation machinery and deregulated synthesis proteins.
IV.
Ribosomopathy refers to a group of diseases caused by the deformed translation machinery, and many RPs are directly involved with ribosomopathy, thus finding the regulatory interaction of miRNAs and RPs could explore the regulatory role of miRNAs on ribosomopathy and might help to develop future therapeutic strategies.
V.
Deregulation of both RPs and miRNAs is very common in diseases including almost all types of cancers. Investigation of the miRNAs mediated regulation of RPs could provide a reasonable explanation behind the pathological conditions of these diseases.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4409/10/1/110/s1, Supplementary Figure S1. The RNA-seq heatmap showing the expression status of RPs in 300 ovarian cancer patients, Supplementary Figure S2. Interaction network between ribosomal proteins (RPs) and microRNAs (miRNAs). The extensive network is showing that more than a thousand miRNAs are connected to the 72 RPs, Supplementary Table S1. Involvement of Ribosomal Proteins (RPs) in different cellular components, Supplementary Table S2. Involvement of Ribosomal Proteins (RPs) in different Molecular Functions, and Supplementary Table S3. Top 15 ribosomal proteins (RP) in terms of being targeted by the numbers of miRNAs.

Author Contributions

A.M.M.T.R. performed the literature search, analyzed the information, designed the figures and wrote the manuscript. Y.-G.Y. critically reviewed, made comments and approved the manuscript. Both authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Yangzhou city and Yangzhou University corporation (YZ2020185), the Open Project Program of Jiangsu Key Laboratory of Zoonosis (No. R1807) and Joint International Research Laboratory of Agriculture and Agri-Product Safety, the Ministry of Education of China, Yangzhou University (JRK2018-11/JILAR-KF202015).

Acknowledgments

The results shown here are in part based upon the data generated by the ‘cBioPortal for Cancer Genomics (http://www.cbioportal.org/index.do) database’, which is a component of ‘the cancer genome atlas (TCGA) Research Network (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga)’.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Ban, N.; Beckmann, R.; Cate, J.H.; Dinman, J.D.; Dragon, F.; Ellis, S.R.; Lafontaine, D.L.; Lindahl, L.; Liljas, A.; Lipton, J.M.; et al. A new system for naming ribosomal proteins. Curr. Opin. Struct. Biol. 2014, 24, 165–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Wool, I.G. The Structure and Function of Eukaryotic Ribosomes. Annu. Rev. Biochem. 1979, 48, 719–754. [Google Scholar] [CrossRef] [PubMed]
  3. Xue, S.; Barna, M. Specialized ribosomes: A new frontier in gene regulation and organismal biology. Nat. Rev. Mol. Cell. Biol. 2012, 13, 355–369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Genuth, N.R.; Barna, M. Heterogeneity and specialized functions of translation machinery: From genes to organisms. Nat. Rev. Genet. 2018, 19, 431–452. [Google Scholar] [CrossRef]
  5. Genuth, N.R.; Barna, M. The discovery of ribosome heterogeneity and its implications for gene regulation and organismal life. Mol. Cell. 2018, 71, 364–374. [Google Scholar] [CrossRef] [Green Version]
  6. Hausser, J.; Syed, A.P.; Bilen, B.; Zavolan, M. Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation. Genome Res. 2013, 23, 604–615. [Google Scholar] [CrossRef] [Green Version]
  7. Orom, U.A.; Nielsen, F.C.; Lund, A.H. MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol. Cell 2008, 30, 460–471. [Google Scholar] [CrossRef]
  8. Lewis, B.P.; Burge, C.B.; Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005, 120, 15–20. [Google Scholar] [CrossRef] [Green Version]
  9. Reza, A.M.M.T.; Choi, Y.J.; Yuan, Y.G.; Das, J.; Yasuda, H.; Kim, J.H. MicroRNA-7641 is a regulator of ribosomal proteins and a promising targeting factor to improve the efficacy of cancer therapy. Sci. Rep. 2017, 7, 8365. [Google Scholar] [CrossRef] [Green Version]
  10. Ni, W.J.; Leng, X.M. miRNA-dependent activation of mRNA translation. MicroRNA 2016, 5, 83–86. [Google Scholar] [CrossRef]
  11. Iwakawa, H.O.; Tomari, Y. The functions of microRNAs: mRNA decay and translational repression. Trends Cell. Biol. 2015, 25, 651–665. [Google Scholar] [CrossRef] [PubMed]
  12. O’Brien, J.; Hayder, H.; Zayed, Y.; Peng, C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. 2018, 9, 402. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Macfarlane, L.-A.; Murphy, P.R. MicroRNA: Biogenesis, function and role in cancer. Curr. Genom. 2010, 11, 537–561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Ha, M.; Kim, V.N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell. Biol. 2014, 15, 509–524. [Google Scholar] [CrossRef]
  15. Treiber, T.; Treiber, N.; Meister, G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nat. Rev. Mol. Cell. Biol. 2019, 20, 5–20. [Google Scholar] [CrossRef]
  16. Fabian, M.R.; Sonenberg, N.; Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 2010, 79, 351–379. [Google Scholar] [CrossRef] [Green Version]
  17. Dalmay, T. Mechanism of miRNA-mediated repression of mRNA translation. Essays Biochem. 2013, 54, 29–38. [Google Scholar]
  18. Cannell, I.G.; Kong, Y.W.; Bushell, M. How do microRNAs regulate gene expression? Biochem. Soc. Trans. 2008, 36, 1224–1231. [Google Scholar] [CrossRef] [Green Version]
  19. Chaillou, T.; Kirby, T.J.; McCarthy, J.J. Ribosome biogenesis: Emerging evidence for a central role in the regulation of skeletal muscle mass. J. Cell. Physiol. 2014, 229, 1584–1594. [Google Scholar] [CrossRef] [Green Version]
  20. Lempiainen, H.; Shore, D. Growth control and ribosome biogenesis. Curr. Opin. Cell. Biol. 2009, 21, 855–863. [Google Scholar] [CrossRef]
  21. Mayer, C.; Grummt, I. Ribosome biogenesis and cell growth: mTOR coordinates transcription by all three classes of nuclear RNA polymerases. Oncogene 2006, 25, 6384–6391. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Sanchez, C.G.; Teixeira, F.K.; Czech, B.; Preall, J.B.; Zamparini, A.L.; Seifert, J.R.; Malone, C.D.; Hannon, G.J.; Lehmann, R. Regulation of ribosome biogenesis and protein synthesis controls germline stem cell differentiation. Cell. Stem. Cell. 2016, 18, 276–290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Ebright, R.Y.; Lee, S.; Wittner, B.S.; Niederhoffer, K.L.; Nicholson, B.T.; Bardia, A.; Truesdell, S.; Wiley, D.F.; Wesley, B.; Li, S.; et al. Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis. Science. 2020, 367, 1468–1473. [Google Scholar] [CrossRef] [PubMed]
  24. Wang, W.; Nag, S.; Zhang, X.; Wang, M.H.; Wang, H.; Zhou, J.; Zhang, R. Ribosomal proteins and human diseases: Pathogenesis, molecular mechanisms, and therapeutic implications. Med. Res. Rev. 2015, 35, 225–285. [Google Scholar] [CrossRef] [PubMed]
  25. Thomson, E.; Ferreira-Cerca, S.; Hurt, E. Eukaryotic ribosome biogenesis at a glance. J. Cell Sci. 2013, 126, 4815–4821. [Google Scholar] [CrossRef] [Green Version]
  26. Kressler, D.; Hurt, E.; Baβler, J. Driving ribosome assembly. Biochim. Biophys. Acta. 2010, 1803, 673–683. [Google Scholar] [CrossRef] [Green Version]
  27. Nikolay, R.; van den Bruck, D.; Achenbach, J.; Nierhaus, K.H. Ribosomal proteins: Role in ribosomal functions. In eLS; John Wiley & Sons, Ltd.: Chichester, UK, 2015. [Google Scholar]
  28. Martin-Marcos, P.; Hinnebusch, A.G.; Tamame, M. Ribosomal protein L33 is required for ribosome biogenesis, subunit joining, and repression of GCN4 translation. Mol. Cell. Biol. 2007, 27, 5968–5985. [Google Scholar] [CrossRef] [Green Version]
  29. Murguia, J.R.; Serrano, R. New functions of protein kinase Gcn2 in yeast and mammals. IUBMB Life 2012, 64, 971–974. [Google Scholar] [CrossRef]
  30. Tobin, C.; Mandava, C.S.; Ehrenberg, M.; Andersson, D.I.; Sanyal, S. Ribosomes lacking protein S20 are defective in mRNA binding and subunit association. J. Mol. Biol. 2010, 397, 767–776. [Google Scholar] [CrossRef]
  31. Moritz, M.; Paulovich, A.G.; Tsay, Y.F.; Woolford, J.L., Jr. Depletion of yeast ribosomal proteins L16 or rp59 disrupts ribosome assembly. J. Cell Biol. 1990, 111, 2261–2674. [Google Scholar] [CrossRef]
  32. Deshmukh, M.; Tsay, Y.F.; Paulovich, A.G.; Woolford, J.L., Jr. Yeast ribosomal protein L1 is required for the stability of newly synthesized 5S rRNA and the assembly of 60S ribosomal subunits. Mol. Cell. Biol. 1993, 13, 2835–2845. [Google Scholar] [CrossRef] [PubMed]
  33. Deshmukh, M.; Stark, J.; Yeh, L.C.; Lee, J.C.; Woolford, J.L., Jr. Multiple regions of yeast ribosomal protein L1 are important for its interaction with 5S rRNA and assembly into ribosomes. J. Biol. Chem. 1995, 270, 30148–30156. [Google Scholar] [PubMed] [Green Version]
  34. Naganathan, A.; Wood, M.P.; Moore, S.D. The large ribosomal subunit protein L9 enables the growth of EF-P deficient cells and enhances small subunit maturation. PLoS ONE 2015, 10, e0120060. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Ferreira-Cerca, S.; Pöll, G.; Gleizes, P.E.; Tschochner, H.; Milkereit, P. Roles of eukaryotic ribosomal proteins in maturation and transport of pre-18S rRNA and ribosome function. Mol. Cell. 2005, 20, 263–275. [Google Scholar] [CrossRef] [PubMed]
  36. Takyar, S.; Hickerson, R.P.; Noller, H.F. mRNA helicase activity of the ribosome. Cell 2005, 120, 49–58. [Google Scholar] [CrossRef] [Green Version]
  37. Kramer, G.; Rauch, T.; Rist, W.; Vorderwülbecke, S.; Patzelt, H.; Schulze-Specking, A.; Ban, N.; Deuerling, E.; Bukau, B. L23 protein functions as a chaperone docking site on the ribosome. Nature 2002, 419, 171–174. [Google Scholar] [CrossRef]
  38. Pool, M.R.; Stumm, J.; Fulga, T.A.; Sinning, I.; Dobberstein, B. Distinct modes of signal recognition particle interaction with the ribosome. Science 2002, 297, 1345–1348. [Google Scholar] [CrossRef]
  39. Beckmann, R.; Spahn, C.M.; Eswar, N.; Helmers, J.; Penczek, P.A.; Sali, A.; Frank, J.; Blobel, G. Architecture of the protein-conducting channel associated with the translating 80S ribosome. Cell 2001, 107, 361–372. [Google Scholar] [CrossRef] [Green Version]
  40. Clemons, W.M.; Ménétret, J.F.; Akey, C.W.; Rapoport, T.A. Structural insight into the protein translocation channel. Curr. Opin. Struct. Biol. 2004, 14, 390–396. [Google Scholar] [CrossRef]
  41. Alksne, L.E.; Anthony, R.A.; Liebman, S.W.; Warner, J.R. An accuracy center in the ribosome conserved over 2 billion years. Proc. Natl. Acad. Sci. USA 1993, 90, 9538–9541. [Google Scholar] [CrossRef] [Green Version]
  42. Stansfield, I.; Jones, K.M.; Herbert, P.; Lewendon, A.; Shaw, W.V.; Tuite, M.F. Missense translation errors in Saccharomyces cerevisiae. J. Mol. Biol. 1998, 282, 13–24. [Google Scholar] [CrossRef] [PubMed]
  43. Synetos, D.; Frantziou, C.P.; Alksne, L.E. Mutations in yeast ribosomal proteins S28 and S4 affect the accuracy of translation and alter the sensitivity of the ribosomes to paromomycin. Biochim. Biophys. Acta 1996, 1309, 156–166. [Google Scholar] [CrossRef]
  44. Rother, S.; Strasser, K. The RNA polymerase II CTD kinase Ctk1 functions in translation elongation. Genes Dev. 2007, 21, 1409–1421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Peltz, S.W.; Hammell, A.B.; Cui, Y.; Yasenchak, J.; Puljanowski, L.; Dinman, J.D. Ribosomal protein L3 mutants alter translational fidelity and promote rapid loss of the yeast killer virus. Mol. Cell. Biol. 1999, 19, 384–391. [Google Scholar] [CrossRef] [Green Version]
  46. Dresios, J.; Panopoulos, P.; Suzuki, K.; Synetos, D. A dispensable yeast ribosomal protein optimizes peptidyltransferase activity and affects translocation. J. Biol. Chem. 2003, 278, 3314–3322. [Google Scholar] [CrossRef] [Green Version]
  47. Meskauskas, A.; Dinman, J.D. Ribosomal protein L5 helps anchor peptidyl-tRNA to the P-site in Saccharomyces cerevisiae. RNA 2001, 7, 1084–1096. [Google Scholar] [CrossRef] [Green Version]
  48. Gadal, O.; Strauss, D.; Kessl, J.; Trumpower, B.; Tollervey, D.; Hurt, E. Nuclear export of 60s ribosomal subunits depends on Xpo1p and requires a nuclear export sequence-containing factor, Nmd3p, that associates with the large subunit protein Rpl10p. Mol. Cell. Biol. 2001, 21, 3405–3415. [Google Scholar] [CrossRef] [Green Version]
  49. Hedges, J.; Hedges, J.; West, M.; Johnson, A.W. Release of the export adapter, Nmd3p, from the 60S ribosomal subunit requires Rpl10p and the cytoplasmic GTPase Lsg1p. EMBO J. 2005, 24, 567–579. [Google Scholar] [CrossRef] [Green Version]
  50. Johnson, A.W.; Lund, E.; Dahlberg, J. Nuclear export of ribosomal subunits. Trends Biochem. Sci. 2002, 27, 580–585. [Google Scholar] [CrossRef]
  51. Briones, E.; Briones, C.; Remacha, M.; Ballesta, J.P. The GTPase center protein L12 is required for correct ribosomal stalk assembly but not for Saccharomyces cerevisiae viability. J. Biol. Chem. 1998, 273, 31956–31961. [Google Scholar] [CrossRef] [Green Version]
  52. Tsay, Y.F.; Shankweiler, G.; Lake, J.; Woolford, J.L., Jr. Localization of Saccharomyces cerevisiae ribosomal protein L16 on the surface of 60 S ribosomal subunits by immunoelectron microscopy. J. Biol. Chem. 1994, 269, 7579–7586. [Google Scholar] [PubMed]
  53. Jakovljevic, J.; de Mayolo, P.A.; Miles, T.D.; Nguyen, T.M.; Léger-Silvestre, I.; Gas, N.; Woolford, J.L., Jr. The carboxy-terminal extension of yeast ribosomal protein S14 is necessary for maturation of 43S preribosomes. Mol. Cell. 2004, 14, 331–342. [Google Scholar] [CrossRef]
  54. Ford, C.L.; Randal-Whitis, L.; Ellis, S.R. Yeast proteins related to the p40/laminin receptor precursor are required for 20S ribosomal RNA processing and the maturation of 40S ribosomal subunits. Cancer Res. 1999, 59, 704–710. [Google Scholar] [PubMed]
  55. Tabb-Massey, A.; Caffrey, J.M.; Logsden, P.; Taylor, S.; Trent, J.O.; Ellis, S.R. Ribosomal proteins Rps0 and Rps21 of Saccharomyces cerevisiae have overlapping functions in the maturation of the 3′ end of 18S rRNA. Nucleic Acids Res. 2003, 31, 6798–6805. [Google Scholar] [CrossRef] [Green Version]
  56. Van Beekvelt, C.A.; de Graaff-Vincent, M.; Faber, A.W.; van’t Riet, J.; Venema, J.; Raué, H.A. All three functional domains of the large ribosomal subunit protein L25 are required for both early and late pre-rRNA processing steps in Saccharomyces cerevisiae. Nucleic Acids Res. 2001, 29, 5001–5008. [Google Scholar] [CrossRef]
  57. Leger-Silvestre, I.; Milkereit, P.; Ferreira-Cerca, S.; Saveanu, C.; Rousselle, J.C.; Choesmel, V.; Guinefoleau, C.; Gas, N.; Gleizes, P.E. The ribosomal protein Rps15p is required for nuclear exit of the 40S subunit precursors in yeast. EMBO J. 2004, 23, 2336–2347. [Google Scholar] [CrossRef] [Green Version]
  58. Vallabhaneni, H.; Farabaugh, P.J. Accuracy modulating mutations of the ribosomal protein S4-S5 interface do not necessarily destabilize the rps4-rps5 protein-protein interaction. RNA 2009, 15, 1100–1109. [Google Scholar] [CrossRef] [Green Version]
  59. Agarwal, D.; Gregory, S.T.; O’Connor, M. Error-prone and error-restrictive mutations affecting ribosomal protein S12. J. Mol. Biol. 2011, 410, 1–9. [Google Scholar] [CrossRef]
  60. Zaher, H.S.; Green, R. Hyperaccurate and error-prone ribosomes exploit distinct mechanisms during tRNA selection. Mol. Cell. 2010, 39, 110–120. [Google Scholar] [CrossRef] [Green Version]
  61. Dresios, J.; Derkatch, I.L.; Liebman, S.W.; Synetos, D. Yeast ribosomal protein L24 affects the kinetics of protein synthesis and ribosomal protein L39 improves translational accuracy, while mutants lacking both remain viable. Biochemistry. 2000, 39, 7236–7244. [Google Scholar] [CrossRef]
  62. Deisenroth, C.; Franklin, D.A.; Zhang, Y. The evolution of the ribosomal protein-MDM2-p53 pathway. Cold Spring Harb. Perspect. Med. 2016, 6, a026138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Liu, Y.; Deisenroth, C.; Zhang, Y. RP-MDM2-p53 pathway: Linking ribosomal biogenesis and tumor surveillance. Trends Cancer 2016, 2, 191–204. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Xu, X.; Xiong, X.; Sun, Y. The role of ribosomal proteins in the regulation of cell proliferation, tumorigenesis, and genomic integrity. Sci. China Life Sci. 2016, 59, 656–672. [Google Scholar] [CrossRef] [PubMed]
  65. Kampen, K.R.; Sulima, S.O.; Vereecke, S.; De Keersmaecker, K. Hallmarks of ribosomopathies. Nucleic Acids Res. 2020, 48, 1013–1028. [Google Scholar] [CrossRef] [PubMed]
  66. Arthurs, C.; Murtaza, B.N.; Thomson, C.; Dickens, K.; Henrique, R.; Patel, H.R.H.; Beltran, M.; Millar, M.; Thrasivoulou, C.; Ahmed, A. Expression of ribosomal proteins in normal and cancerous human prostate tissue. PLoS ONE 2017, 12, e0186047. [Google Scholar] [CrossRef] [Green Version]
  67. Nakhoul, H.; Ke, J.; Zhou, X.; Liao, W.; Zeng, S.X.; Lu, H. Ribosomopathies: Mechanisms of disease. Clin. Med. Insights. Blood Disord. 2014, 7, 7–16. [Google Scholar] [CrossRef]
  68. Narla, A.; Ebert, B.L. Ribosomopathies: Human disorders of ribosome dysfunction. Blood 2010, 115, 3196–3205. [Google Scholar] [CrossRef]
  69. De Keersmaecker, K. A novel mouse model provides insights into the neutropenia associated with the ribosomopathy Shwachman-Diamond syndrome. Haematologica 2015, 100, 1237–1239. [Google Scholar] [CrossRef] [Green Version]
  70. Vlachos, A.; Ball, S.; Dahl, N.; Alter, B.P.; Sheth, S.; Ramenghi, U.; Meerpohl, J.; Karlsson, S.; Liu, J.M.; Leblanc, T.; et al. Diagnosing and treating diamond blackfan anaemia: Results of an international clinical consensus conference. Br. J. Haematol. 2008, 142, 859–876. [Google Scholar] [CrossRef]
  71. Vlachos, A.; Muir, E. How I treat Diamond-Blackfan anemia. Blood 2010, 116, 3715–3723. [Google Scholar] [CrossRef] [Green Version]
  72. Horos, R.; von Lindern, M. Molecular mechanisms of pathology and treatment in Diamond Blackfan Anaemia. Br. J. Haematol. 2012, 159, 514–527. [Google Scholar] [CrossRef] [PubMed]
  73. Padron, E.; Komrokji, R.; List, A.F. Biology and treatment of the 5q- syndrome. Expert Rev. Hematol. 2011, 4, 61–69. [Google Scholar] [CrossRef] [PubMed]
  74. Finch, A.J.; Hilcenko, C.; Basse, N.; Drynan, L.F.; Goyenechea, B.; Menne, T.F.; González Fernández, A.; Simpson, P.; D’Santos, C.S.; Arends, M.J.; et al. Uncoupling of GTP hydrolysis from eIF6 release on the ribosome causes Shwachman-Diamond syndrome. Genes Dev. 2011, 25, 917–929. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Mason, P.J.; Bessler, M. The genetics of dyskeratosis congenita. Cancer Genet. 2011, 204, 635–645. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Thiel, C.T.; Rauch, A. The molecular basis of the cartilage-hair hypoplasia-anauxetic dysplasia spectrum. Best. Pr. Res. Clin. Endocrinol. Metab. 2011, 25, 131–142. [Google Scholar] [CrossRef] [PubMed]
  77. Schlump, J.U.; Stein, A.; Hehr, U.; Karen, T.; Möller-Hartmann, C.; Elcioglu, N.H.; Bogdanova, N.; Woike, H.F.; Lohmann, D.R.; Felderhoff-Mueser, U.; et al. Treacher Collins syndrome: Clinical implications for the paediatrician—a new mutation in a severely affected newborn and comparison with three further patients with the same mutation, and review of the literature. Eur. J. Pediatr. 2012, 171, 1611–1618. [Google Scholar] [CrossRef] [PubMed]
  78. Sondalle, S.B.; Baserga, S.J. Human diseases of the SSU processome. Biochim. Biophys. Acta. 2014, 1842, 758–764. [Google Scholar] [CrossRef] [Green Version]
  79. Armistead, J.; Khatkar, S.; Meyer, B.; Mark, B.L.; Patel, N.; Coghlan, G.; Lamont, R.E.; Liu, S.; Wiechert, J.; Cattini, P.A.; et al. Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen-Conradi syndrome. Am. J. Hum. Genet. 2009, 84, 728–739. [Google Scholar] [CrossRef] [Green Version]
  80. Meyer, B.; Wurm, J.P.; Kötter, P.; Leisegang, M.S.; Schilling, V.; Buchhaupt, M.; Held, M.; Bahr, U.; Karas, M.; Heckel, A.; et al. The Bowen-Conradi syndrome protein Nep1 (Emg1) has a dual role in eukaryotic ribosome biogenesis, as an essential assembly factor and in the methylation of Psi1191 in yeast 18S rRNA. Nucleic Acids Res. 2011, 39, 1526–1537. [Google Scholar] [CrossRef]
  81. Chagnon, P.; Michaud, J.; Mitchell, G.; Mercier, J.; Marion, J.F.; Drouin, E.; Rasquin-Weber, A.; Hudson, T.J.; Richter, A. A missense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. Am. J. Hum. Genet. 2002, 71, 1443–1449. [Google Scholar] [CrossRef] [Green Version]
  82. Freed, E.F.; Prieto, J.L.; McCann, K.L.; McStay, B.; Baserga, S.J. NOL11, implicated in the pathogenesis of North American Indian childhood cirrhosis, is required for pre-rRNA transcription and processing. PLoS Genet. 2012, 8, e1002892. [Google Scholar] [CrossRef] [PubMed]
  83. Chen, B.; Zhang, W.; Gao, J.; Chen, H.; Jiang, L.; Liu, D.; Cao, Y.; Zhao, S.; Qiu, Z.; Zeng, J. Downregulation of ribosomal protein S6 inhibits the growth of non-small cell lung cancer by inducing cell cycle arrest, rather than apoptosis. Cancer Lett. 2014, 354, 378–389. [Google Scholar] [CrossRef] [PubMed]
  84. Ning, Q.; Pang, Y.; Shao, S.; Luo, M.; Zhao, L.; Hu, T.; Zhao, X. MicroRNA-147b suppresses the proliferation and invasion of non-small-cell lung cancer cells through downregulation of Wnt/beta-catenin signalling via targeting of RPS15A. Clin. Exp. Pharm. Physiol. 2020, 47, 449–458. [Google Scholar] [CrossRef] [PubMed]
  85. Tsofack, S.P.; Meunier, L.; Sanchez, L.; Madore, J.; Provencher, D.; Mes-Masson, A.M.; Lebel, M. Low expression of the X-linked ribosomal protein S4 in human serous epithelial ovarian cancer is associated with a poor prognosis. BMC Cancer 2013, 13, 303. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Paquet, É.R.; Hovington, H.; Brisson, H.; Lacombe, C.; Larue, H.; Têtu, B.; Lacombe, L.; Fradet, Y.; Lebel, M. Low level of the X-linked ribosomal protein S4 in human urothelial carcinomas is associated with a poor prognosis. Biomark. Med. 2015, 9, 187–197. [Google Scholar] [CrossRef]
  87. Maruyama, Y.; Miyazaki, T.; Ikeda, K.; Okumura, T.; Sato, W.; Horie-Inoue, K.; Okamoto, K.; Takeda, S.; Inoue, S. Short hairpin RNA library-based functional screening identified ribosomal protein L31 that modulates prostate cancer cell growth via p53 pathway. PLoS ONE 2014, 9, e108743. [Google Scholar] [CrossRef]
  88. Fan, H.; Li, J.; Jia, Y.; Wu, J.; Yuan, L.; Li, M.; Wei, J.; Xu, B. Silencing of ribosomal protein L34 (RPL34) inhibits the proliferation and invasion of esophageal cancer cells. Oncol. Res. 2017, 25, 1061–1068. [Google Scholar] [CrossRef]
  89. Rao, S.; Cai, K.Q.; Stadanlick, J.E.; Greenberg-Kushnir, N.; Solanki-Patel, N.; Lee, S.Y.; Fahl, S.P.; Testa, J.R.; Wiest, D.L. Ribosomal protein Rpl22 controls the dissemination of T-cell lymphoma. Cancer Res. 2016, 76, 3387–3396. [Google Scholar] [CrossRef] [Green Version]
  90. Nieminen, T.T.; O’Donohue, M.F.; Wu, Y.; Lohi, H.; Scherer, S.W.; Paterson, A.D.; Ellonen, P.; Abdel-Rahman, W.M.; Valo, S.; Mecklin, J.P.; et al. Germline mutation of RPS20, encoding a ribosomal protein, causes predisposition to hereditary nonpolyposis colorectal carcinoma without DNA mismatch repair deficiency. Gastroenterology 2014, 147, 595–598. [Google Scholar] [CrossRef] [Green Version]
  91. Ruggero, D.; Shimamura, A. Marrow failure: A window into ribosome biology. Blood 2014, 124, 2784. [Google Scholar] [CrossRef] [Green Version]
  92. Burwick, N.; Shimamura, A.; Liu, J.M. Non-Diamond Blackfan anemia disorders of ribosome function: Shwachman Diamond syndrome and 5q- syndrome. Semin. Hematol. 2011, 48, 136–143. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Dror, Y.; Donadieu, J.; Koglmeier, J.; Dodge, J.; Toiviainen-Salo, S.; Makitie, O.; Kerr, E.; Zeidler, C.; Shimamura, A.; Shah, N.; et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann. N. Y. Acad. Sci. 2011, 1242, 40–55. [Google Scholar] [CrossRef] [PubMed]
  94. Myers, K.C.; Davies, S.M.; Shimamura, A. Clinical and molecular pathophysiology of Shwachman-Diamond syndrome: An update. Hematol. Oncol. Clin. North Am. 2013, 27, 117–128. [Google Scholar] [CrossRef] [Green Version]
  95. Ajore, R.; Raiser, D.; McConkey, M.; Jöud, M.; Boidol, B.; Mar, B.; Saksena, G.; Weinstock, D.M.; Armstrong, S.; Ellis, S.R.; et al. Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations. EMBO Mol. Med. 2017, 9, 498–507. [Google Scholar] [CrossRef] [PubMed]
  96. Amsterdam, A.; Sadler, K.C.; Lai, K.; Farrington, S.; Bronson, R.T.; Lees, J.A.; Hopkins, N. Many ribosomal protein genes are cancer genes in zebrafish. PLoS Biol. 2004, 2, e139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Kazerounian, S.; Ciarlini, P.; Ghazvinian, R.; Alberich-Jorda, M.; Yuan, D.; Joshi, M.; Zhang, H.; Beggs, A.; Gazda, H.T. Increased tumorigenesis in ribosomal proteins L5 and S24 heterozygous mice. Blood 2013, 122, 1227. [Google Scholar] [CrossRef]
  98. Loreni, F.; Mancino, M.; Biffo, S. Translation factors and ribosomal proteins control tumor onset and progression: How? Oncogene 2014, 33, 2145–2156. [Google Scholar] [CrossRef] [Green Version]
  99. Henry, J.L.; Coggin, D.L.; King, C.R. High-level expression of the ribosomal protein L19 in human breast tumors that overexpress erbB-2. Cancer Res. 1993, 53, 1403–1408. [Google Scholar]
  100. Dressman, M.A.; Baras, A.; Malinowski, R.; Alvis, L.B.; Kwon, I.; Walz, T.M.; Polymeropoulos, M.H. Gene expression profiling detects gene amplification and differentiates tumor types in breast cancer. Cancer Res. 2003, 63, 2194–2199. [Google Scholar]
  101. Shi, Y.; Zhai, H.; Wang, X.; Han, Z.; Liu, C.; Lan, M.; Du, J.; Guo, C.; Zhang, Y.; Wu, K.; et al. Ribosomal proteins S13 and L23 promote multidrug resistance in gastric cancer cells by suppressing drug-induced apoptosis. Exp. Cell. Res. 2004, 296, 337–346. [Google Scholar] [CrossRef]
  102. Xie, X.; Guo, P.; Yu, H.; Wang, Y.; Chen, G. Ribosomal proteins: Insight into molecular roles and functions in hepatocellular carcinoma. Oncogene 2018, 37, 277–285. [Google Scholar] [CrossRef] [PubMed]
  103. Lai, M.D.; Xu, J. Ribosomal proteins and colorectal cancer. Curr. Genom. 2007, 8, 43–49. [Google Scholar]
  104. Kasai, H.; Nadano, D.; Hidaka, E.; Higuchi, K.; Kawakubo, M.; Sato, T.A.; Nakayama, J. Differential expression of ribosomal proteins in human normal and neoplastic colorectum. J. Histochem. Cytochem. 2003, 51, 567–574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  105. Huang, C.J.; Chien, C.C.; Yang, S.H.; Chang, C.C.; Sun, H.L.; Cheng, Y.C.; Liu, C.C.; Lin, S.C.; Lin, C.M. Faecal ribosomal protein L19 is a genetic prognostic factor for survival in colorectal cancer. J. Cell. Mol. Med. 2008, 12, 1936–1943. [Google Scholar] [CrossRef] [PubMed]
  106. Bee, A.; Ke, Y.; Forootan, S.; Lin, K.; Beesley, C.; Forrest, S.E.; Foster, C.S. Ribosomal protein l19 is a prognostic marker for human prostate cancer. Clin. Cancer Res. 2006, 12, 2061–2065. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Guimaraes, J.C.; Zavolan, M. Patterns of ribosomal protein expression specify normal and malignant human cells. Genome Biol. 2016, 17, 1–13. [Google Scholar] [CrossRef] [Green Version]
  108. Hollis, A.R.; Starkey, M.P. MicroRNAs in equine veterinary science. Equine Vet. J. 2018, 50, 721–726. [Google Scholar] [CrossRef]
  109. Reza, A.M.M.T.; Choi, Y.J.; Han, S.G.; Song, H.; Park, C.; Hong, K.; Kim, J.H. Roles of microRNAs in mammalian reproduction: From the commitment of germ cells to peri-implantation embryos. Biol. Rev. 2019, 94, 415–438. [Google Scholar] [CrossRef]
  110. Rajman, M.; Schratt, G. MicroRNAs in neural development: From master regulators to fine-tuners. Development 2017, 144, 2310. [Google Scholar] [CrossRef] [Green Version]
  111. Burgos-Aceves, M.A.; Cohen, A.; Smith, Y.; Faggio, C. A potential microRNA regulation of immune-related genes in invertebrate haemocytes. Sci. Total Environ. 2018, 621, 302–307. [Google Scholar] [CrossRef]
  112. Nejad, C.; Stunden, H.J.; Gantier, M.P. A guide to miRNAs in inflammation and innate immune responses. FEBS J. 2018, 285, 3695–3716. [Google Scholar] [CrossRef] [PubMed]
  113. Wu, C.J.; Lu, L.F. MicroRNA in immune Regulation. Curr. Top. Microbiol. Immunol. 2017, 410, 249–267. [Google Scholar] [PubMed]
  114. Kim, D.Y.; Sung, J.H. Regulatory role of microRNAs in the proliferation and differentiation of adipose-derived stem cells. Histol. Histopathol. 2017, 32, 1–10. [Google Scholar] [PubMed]
  115. Yu, X.; An, J.; Hua, Y.; Li, Z.; Yan, N.; Fan, W.; Su, C. MicroRNA-194 regulates keratinocyte proliferation and differentiation by targeting Grainyhead-like 2 in psoriasis. Pathol. Res. Pr. 2017, 213, 89–97. [Google Scholar] [CrossRef]
  116. Zhang, W.M.; Zhang, Z.R.; Yang, X.T.; Zhang, Y.G.; Gao, Y.S. Overexpression of miR21 promotes neural stem cell proliferation and neural differentiation via the Wnt/betacatenin signaling pathway in vitro. Mol. Med. Rep. 2018, 17, 330–335. [Google Scholar]
  117. Zhang, Y.; Shen, B.; Zhang, D.; Wang, Y.; Tang, Z.; Ni, N.; Jin, X.; Luo, M.; Sun, H.; Gu, P. miR-29a regulates the proliferation and differentiation of retinal progenitors by targeting Rbm8a. Oncotarget 2017, 8, 31993–32008. [Google Scholar] [CrossRef] [Green Version]
  118. Ran, X.; Xiao, C.-H.; Xiang, G.-M.; Ran, X.-Z. Regulation of embryonic stem cell self-renewal and differentiation by microRNAs. Cell. Reprogram. 2017, 19, 150–158. [Google Scholar] [CrossRef]
  119. Acunzo, M.; Croce, C.M. MicroRNA in cancer and cachexi—a mini-review. J. Infect. Dis. 2015, 212 (Suppl. 1), S74–S77. [Google Scholar] [CrossRef]
  120. Reza, A.M.M.T.; Choi, Y.J.; Yasuda, H.; Kim, J.H. Human adipose mesenchymal stem cell-derived exosomal-miRNAs are critical factors for inducing anti-proliferation signalling to A2780 and SKOV-3 ovarian cancer cells. Sci. Rep. 2016, 6, 38498. [Google Scholar] [CrossRef]
  121. Rupaimoole, R.; Slack, F.J. MicroRNA therapeutics: Towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 2017, 16, 203–222. [Google Scholar] [CrossRef]
  122. Wu, Q.; Yang, Z.; Shi, Y.; Fan, D. miRNAs in human cancers: The diagnostic and therapeutic implications. Curr. Pharm. Des. 2014, 20, 5336–5347. [Google Scholar] [CrossRef] [PubMed]
  123. Wu, H.H.; Lin, W.C.; Tsai, K.W. Advances in molecular biomarkers for gastric cancer: miRNAs as emerging novel cancer markers. Expert Rev. Mol. Med. 2014, 16, e1. [Google Scholar] [CrossRef] [PubMed]
  124. Teoh, S.L.; Das, S. The role of microRNAs in diagnosis, prognosis, metastasis and resistant cases in breast cancer. Curr. Pharm. Des. 2017, 23, 1845–1859. [Google Scholar] [CrossRef] [PubMed]
  125. Deb, B.; Uddin, A.; Chakraborty, S. miRNAs and ovarian cancer: An overview. J. Cell. Physiol. 2018, 233, 3846–3854. [Google Scholar] [CrossRef]
  126. Qadir, M.I.; Faheem, A. miRNA: A diagnostic and therapeutic tool for pancreatic cancer. Crit. Rev. Eukaryot. Gene Expr. 2017, 27, 197–204. [Google Scholar] [CrossRef]
  127. Williams, M.; Cheng, Y.Y.; Blenkiron, C.; Reid, G. Exploring mechanisms of microRNA downregulation in cancer. MicroRNA 2017, 6, 2–16. [Google Scholar] [CrossRef]
  128. Quinlan, S.; Kenny, A.; Medina, M.; Engel, T.; Jimenez-Mateos, E.M. MicroRNAs in neurodegenerative diseases. Int. Rev. Cell. Mol. Biol. 2017, 334, 309–343. [Google Scholar]
  129. Molasy, M.; Walczak, A.; Szaflik, J.; Szaflik, J.P.; Majsterek, I. MicroRNAs in glaucoma and neurodegenerative diseases. J. Hum. Genet. 2017, 62, 105–112. [Google Scholar] [CrossRef]
  130. Rinchetti, P.; Rizzuti, M.; Faravelli, I.; Corti, S. MicroRNA metabolism and dysregulation in amyotrophic lateral sclerosis. Mol. Neurobiol. 2018, 55, 2617–2630. [Google Scholar] [CrossRef] [Green Version]
  131. Jiang, B.; Huo, Y.; Gu, Y.; Wang, J. The role of microRNAs in myopia. Graefes Arch. Clin. Exp. Ophthalmol. 2017, 255, 7–13. [Google Scholar] [CrossRef]
  132. Pan, Y.B.; Sun, Z.L.; Feng, D.F. The role of microRNA in traumatic brain injury. Neuroscience 2017, 367, 189–199. [Google Scholar] [CrossRef] [PubMed]
  133. Baradan, R.; Hollander, J.M.; Das, S. Mitochondrial miRNAs in diabetes: Just the tip of the iceberg. Can. J. Physiol. Pharm. 2017, 95, 1156–1162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Su, L.C.; Huang, A.F.; Jia, H.; Liu, Y.; Xu, W.D. Role of microRNA-155 in rheumatoid arthritis. Int. J. Rheum. Dis. 2017, 20, 1631–1637. [Google Scholar] [CrossRef] [PubMed]
  135. Tavasolian, F.; Abdollahi, E.; Rezaei, R.; Momtazi-Borojeni, A.A.; Henrotin, Y.; Sahebkar, A. Altered expression of microRNAs in rheumatoid arthritis. J. Cell. Biochem. 2018, 119, 478–487. [Google Scholar] [CrossRef] [PubMed]
  136. Friedrich, M.; Pracht, K.; Mashreghi, M.F.; Jäck, H.M.; Radbruch, A.; Seliger, B. The role of the miR-148/-152 family in physiology and disease. Eur. J. Immunol. 2017, 47, 2026–2038. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Alipoor, S.D.; Adcock, I.M.; Garssen, J.; Mortaz, E.; Varahram, M.; Mirsaeidi, M.; Velayati, A. The roles of miRNAs as potential biomarkers in lung diseases. Eur. J. Pharm. 2016, 791, 395–404. [Google Scholar] [CrossRef] [PubMed]
  138. Seeliger, C.; Balmayor, E.R.; van Griensven, M. miRNAs related to skeletal diseases. Stem. Cells. Dev. 2016, 25, 1261–1281. [Google Scholar] [CrossRef]
  139. Jung, H.J.; Suh, Y. Circulating miRNAs in ageing and ageing-related diseases. J. Genet. Genom. 2014, 41, 465–472. [Google Scholar] [CrossRef] [Green Version]
  140. Kumar, S.; Vijayan, M.; Bhatti, J.S.; Reddy, P.H. MicroRNAs as peripheral biomarkers in aging and age-related diseases. Prog. Mol. Biol. Transl. Sci. 2017, 146, 47–94. [Google Scholar]
  141. Cheng, H.S.; Njock, M.S.; Khyzha, N.; Dang, L.T.; Fish, J.E. Noncoding RNAs regulate NF-κB signaling to modulate blood vessel inflammation. Front. Genet. 2014, 5, 422. [Google Scholar] [CrossRef] [Green Version]
  142. Wang, L.; Meng, X.; Li, G.; Zhou, Q.; Xiao, J. Circular RNAs in cardiovascular diseases. Adv. Exp. Med. Biol. 2018, 1087, 191–204. [Google Scholar] [PubMed]
  143. Bandara, K.V.; Michael, M.Z.; Gleadle, J.M. MicroRNA biogenesis in hypoxia. MicroRNA 2017, 6, 80–96. [Google Scholar] [CrossRef] [PubMed]
  144. Harden, J.T.; Krams, S.M. Micro-RNAs in transplant tolerance. Curr. Opin. Organ Transpl. 2018, 23, 66–72. [Google Scholar] [CrossRef] [PubMed]
  145. Chen, Y.; Li, G.; Liu, M.-L. Microvesicles as emerging biomarkers and therapeutic targets in cardiometabolic diseases. Genom. Proteom. Bioinf. 2018, 16, 50–62. [Google Scholar] [CrossRef]
  146. Arnold, M.L.; Melentijevic, I.; Smart, A.J.; Driscoll, M. Q&A: Trash talk: Disposal and remote degradation of neuronal garbage. BMC Biol. 2018, 16, 17. [Google Scholar]
  147. Qu, Y.; Liu, H.; Lv, X.; Liu, Y.; Wang, X.; Zhang, M.; Zhang, X.; Li, Y.; Lou, Q.; Li, S. MicroRNA-16-5p overexpression suppresses proliferation and invasion as well as triggers apoptosis by targeting VEGFA expression in breast carcinoma. Oncotarget 2017, 8, 72400–72410. [Google Scholar] [CrossRef]
  148. Ruan, L.; Qian, X. MiR-16-5p inhibits breast cancer by reducing AKT3 to restrain NF-κB pathway. Biosci. Rep. 2019, 39 BSR20191611, 1–10. [Google Scholar] [CrossRef] [Green Version]
  149. Cheng, B.; Ding, F.; Huang, C.Y.; Xiao, H.; Fei, F.Y.; Li, J. Role of miR-16-5p in the proliferation and metastasis of hepatocellular carcinoma. Eur. Rev. Med. Pharm. Sci. 2019, 23, 137–145. [Google Scholar]
  150. Munson, P.B.; Hall, E.M.; Farina, N.H.; Pass, H.I.; Shukla, A. Exosomal miR-16-5p as a target for malignant mesothelioma. Sci. Rep. 2019, 9, 11688. [Google Scholar] [CrossRef] [Green Version]
  151. Krell, A.; Wolter, M.; Stojcheva, N.; Hertler, C.; Liesenberg, F.; Zapatka, M.; Weller, M.; Malzkorn, B.; Reifenberger, G. MiR-16-5p is frequently down-regulated in astrocytic gliomas and modulates glioma cell proliferation, apoptosis and response to cytotoxic therapy. Neuropathol. Appl. Neurobiol. 2019, 45, 441–458. [Google Scholar] [CrossRef]
  152. Chava, S.; Reynolds, C.P.; Pathania, A.S.; Gorantla, S.; Poluektova, L.Y.; Coulter, D.W.; Gupta, S.C.; Pandey, M.K.; Challagundla, K.B. miR-15a-5p, miR-15b-5p, and miR-16-5p inhibit tumor progression by directly targeting MYCN in neuroblastoma. Mol. Oncol. 2019, 14, 180–196. [Google Scholar] [CrossRef] [PubMed]
  153. Zhang, H.; Yang, K.; Ren, T.; Huang, Y.; Tang, X.; Guo, W. miR-16-5p inhibits chordoma cell proliferation, invasion and metastasis by targeting Smad3. Cell Death Dis. 2018, 9, 680. [Google Scholar] [CrossRef] [PubMed]
  154. Li, L.; Jia, J.; Liu, X.; Yang, S.; Ye, S.; Yang, W.; Zhang, Y. MicroRNA-16-5p controls development of osteoarthritis by targeting SMAD3 in chondrocytes. Curr. Pharm. Des. 2015, 21, 5160–5167. [Google Scholar] [CrossRef] [PubMed]
  155. Zhu, C.; Huang, Q.; Zhu, H. Melatonin inhibits the proliferation of gastric cancer cells through regulating the miR-16-5p-Smad3 pathway. DNA Cell. Biol. 2018, 37, 244–252. [Google Scholar] [CrossRef] [PubMed]
  156. Sang, S.; Zhang, Z.; Qin, S.; Li, C.; Dong, Y. MicroRNA-16-5p inhibits osteoclastogenesis in giant cell tumor of bone. Biomed. Res. Int. 2017, 2017, 3173547. [Google Scholar] [CrossRef] [Green Version]
  157. Dunaeva, M.; Blom, J.; Thurlings, R.; Pruijn, G.J.M. Circulating serum miR-223-3p and miR-16-5p as possible biomarkers of early rheumatoid arthritis. Clin. Exp. Immunol. 2018, 193, 376–385. [Google Scholar] [CrossRef] [Green Version]
  158. Venza, M.; Visalli, M.; Beninati, C.; Benfatto, S.; Teti, D.; Venza, I. miR-92a-3p and MYCBP2 are involved in MS-275-induced and c-myc-mediated TRAIL-sensitivity in melanoma cells. Int. Immunopharmacol. 2016, 40, 235–243. [Google Scholar] [CrossRef]
  159. Casadei, L.; Calore, F.; Creighton, C.J.; Guescini, M.; Batte, K.; Iwenofu, O.H.; Zewdu, A.; Braggio, D.A.; Bill, K.L.; Fadda, P.; et al. Exosome-derived miR-25-3p and miR-92a-3p stimulate liposarcoma progression. Cancer Res. 2017, 77, 3846–3856. [Google Scholar] [CrossRef] [Green Version]
  160. Song, H.; Zhang, Y.; Liu, N.; Zhao, S.; Kong, Y.; Yuan, L. miR-92a-3p exerts various effects in glioma and glioma stem-like cells specifically targeting CDH1/beta-catenin and Notch-1/Akt signaling pathways. Int. J. Mol. Sci. 2016, 17, 1799. [Google Scholar] [CrossRef]
  161. Sharifi, M.; Salehi, R. Blockage of miR-92a-3p with locked nucleic acid induces apoptosis and prevents cell proliferation in human acute megakaryoblastic leukemia. Cancer Gene 2016, 23, 29–35. [Google Scholar] [CrossRef]
  162. Ahmadi, S.; Sharifi, M.; Salehi, R. Locked nucleic acid inhibits miR-92a-3p in human colorectal cancer, induces apoptosis and inhibits cell proliferation. Cancer Gene 2016, 23, 199–205. [Google Scholar] [CrossRef] [PubMed]
  163. Fu, F.; Jiang, W.; Zhou, L.; Chen, Z. Circulating exosomal miR-17-5p and miR-92a-3p predict pathologic stage and grade of colorectal cancer. Transl. Oncol. 2018, 11, 221–232. [Google Scholar] [CrossRef] [PubMed]
  164. Mao, G.; Zhang, Z.; Hu, S.; Zhang, Z.; Chang, Z.; Huang, Z.; Liao, W.; Kang, Y. Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res. 2018, 9, 247. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  165. Rong, X.; Jia, L.; Hong, L.; Pan, L.; Xue, X.; Zhang, C.; Lu, J.; Jin, Z.; Qiu, H.; Wu, R. Serum miR-92a-3p as a new potential biomarker for diagnosis of Kawasaki disease with coronary artery lesions. J. Cardiovasc. Transl. Res. 2017, 10, 1–8. [Google Scholar] [CrossRef] [PubMed]
  166. Ma, J.; Shang, S.; Wang, J.; Zhang, T.; Nie, F.; Song, X.; Zhao, H.; Zhu, C.; Zhang, R.; Hao, D. Identification of miR-22-3p, miR-92a-3p, and miR-137 in peripheral blood as biomarker for schizophrenia. Psychiatry Res. 2018, 265, 70–76. [Google Scholar] [CrossRef]
  167. Kim, B.S.; Jung, J.Y.; Jeon, J.Y.; Kim, H.A.; Suh, C.H. Circulating hsa-miR-30e-5p, hsa-miR-92a-3p, and hsa-miR-223-3p may be novel biomarkers in systemic lupus erythematosus. HLA 2016, 88, 187–193. [Google Scholar] [CrossRef]
  168. He, J.R.; Zhang, Y.; Lu, W.J.; Liang, H.B.; Tu, X.Q.; Ma, F.Y.; Yang, G.Y.; Zeng, L.L. Age-related frontal periventricular white matter hyperintensities and miR-92a-3p are associated with early-onset post-stroke depression. Front. Aging Neurosci. 2017, 9, 328. [Google Scholar] [CrossRef] [Green Version]
  169. Nabavi, N.; Saidy, N.R.N.; Venalainen, E.; Haegert, A.; Parolia, A.; Xue, H.; Wang, Y.; Wu, R.; Dong, X.; Collins, C.; et al. miR-100-5p inhibition induces apoptosis in dormant prostate cancer cells and prevents the emergence of castration-resistant prostate cancer. Sci. Rep. 2017, 7, 4079. [Google Scholar] [CrossRef] [Green Version]
  170. Chen, P.; Lin, C.; Quan, J.; Lai, Y.; He, T.; Zhou, L.; Pan, X.; Wu, X.; Wang, Y.; Ni, L.; et al. Oncogenic miR-100-5p is associated with cellular viability, migration and apoptosis in renal cell carcinoma. Mol. Med. Rep. 2017, 16, 5023–5030. [Google Scholar] [CrossRef] [Green Version]
  171. Jakob, M.; Mattes, L.M.; Küffer, S.; Unger, K.; Hess, J.; Bertlich, M.; Haubner, F.; Ihler, F.; Canis, M.; Weiss, B.G.; et al. MicroRNA expression patterns in oral squamous cell carcinoma: Hsa-mir-99b-3p and hsa-mir-100-5p as novel prognostic markers for oral cancer. Head Neck 2019, 41, 3499–3515. [Google Scholar] [CrossRef]
  172. Lai, Y.; Kacal, M.; Kanony, M.; Stukan, I.; Jatta, K.; Kis, L.; Norberg, E.; Vakifahmetoglu-Norberg, H.; Lewensohn, R.; Hydbring, P.; et al. miR-100-5p confers resistance to ALK tyrosine kinase inhibitors Crizotinib and Lorlatinib in EML4-ALK positive NSCLC. Biochem. Biophys. Res. Commun. 2019, 511, 260–265. [Google Scholar] [CrossRef] [PubMed]
  173. He, Q.L.; Qin, S.Y.; Tao, L.; Ning, H.J.; Jiang, H.X. Prognostic value and prospective molecular mechanism of miR-100-5p in hepatocellular carcinoma: A comprehensive study based on 1,258 samples. Oncol. Lett. 2019, 18, 6126–6142. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Ye, X.; Luo, H.; Chen, Y.; Wu, Q.; Xiong, Y.; Zhu, J.; Diao, Y.; Wu, Z.; Miao, J.; Wan, J. MicroRNAs 99b-5p/100-5p regulated by endoplasmic reticulum stress are involved in abeta-induced pathologies. Front. Aging Neurosci. 2015, 7, 210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  175. He, Y.; Li, C.; Xu, H.; Duan, Z.; Liu, Y.; Zeng, R.; Li, M.; Wang, B. AKT-dependent hyperproliferation of keratinocytes in familial hidradenitis suppurativa with a NCSTN mutation: A potential role of defective miR-100-5p. Br. J. Derm. 2019, 182, 500–502. [Google Scholar] [CrossRef]
  176. Wang, J.; Liu, L.; Sun, Y.; Xue, Y.; Qu, J.; Pan, S.; Li, H.; Qu, H.; Wang, J.; Zhang, J. miR-615-3p promotes proliferation and migration and inhibits apoptosis through its potential target CELF2 in gastric cancer. Biomed. Pharm. 2018, 101, 406–413. [Google Scholar] [CrossRef]
  177. Laursen, E.B.; Fredsøe, J.; Schmidt, L.; Strand, S.H.; Kristensen, H.; Rasmussen, A.K.I.; Daugaard, T.F.; Mouritzen, P.; Høyer, S.; Kristensen, G.; et al. Elevated miR-615-3p expression predicts adverse clinical outcome and promotes proliferation and migration of prostate cancer cells. Am. J. Pathol. 2019, 189, 2377–2388. [Google Scholar] [CrossRef] [Green Version]
  178. Pu, H.Y.; Xu, R.; Zhang, M.Y.; Yuan, L.J.; Hu, J.Y.; Huang, G.L.; Wang, H.Y. Identification of microRNA-615-3p as a novel tumor suppressor in non-small cell lung cancer. Oncol. Lett. 2017, 13, 2403–2410. [Google Scholar] [CrossRef] [Green Version]
  179. Liu, J.; Jia, Y.; Jia, L.; Li, T.; Yang, L.; Zhang, G. MicroRNA 615-3p inhibits the tumor growth and metastasis of NSCLC via inhibiting IGF2. Oncol. Res. 2019, 27, 269–279. [Google Scholar] [CrossRef]
  180. Sun, Y.; Wang, J.; Pan, S.; Yang, T.; Sun, X.; Wang, Y.; Shi, X.; Zhao, X.; Guo, J.; Zhang, X. LINC00657 played oncogenic roles in esophageal squamous cell carcinoma by targeting miR-615-3p and JunB. Biomed. Pharm. 2018, 108, 316–324. [Google Scholar] [CrossRef]
  181. Mukai, R.; Tomimaru, Y.; Nagano, H.; Eguchi, H.; Mimori, K.; Tomokuni, A.; Asaoka, T.; Wada, H.; Kawamoto, K.; Marubashi, S.; et al. miR-615-3p expression level in bone marrow is associated with tumor recurrence in hepatocellular carcinoma. Mol. Clin. Oncol. 2015, 3, 487–494. [Google Scholar] [CrossRef]
  182. Hu, Y.; Xie, H.; Liu, Y.; Liu, W.; Liu, M.; Tang, H. miR-484 suppresses proliferation and epithelial-mesenchymal transition by targeting ZEB1 and SMAD2 in cervical cancer cells. Cancer Cell. Int. 2017, 17, 36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  183. Hu, Y.; Wu, F.; Liu, Y.; Zhao, Q.; Tang, H. DNMT1 recruited by EZH2-mediated silencing of miR-484 contributes to the malignancy of cervical cancer cells through MMP14 and HNF1A. Clin. Epigenetics 2019, 11, 186. [Google Scholar] [CrossRef] [PubMed]
  184. Zare, A.; Ahadi, A.; Larki, P.; Omrani, M.D.; Zali, M.R.; Alamdari, N.M.; Ghaedi, H. The clinical significance of miR-335, miR-124, miR-218 and miR-484 downregulation in gastric cancer. Mol. Biol. Rep. 2018, 45, 1587–1595. [Google Scholar] [CrossRef] [PubMed]
  185. Yi, R.; Feng, J.; Yang, S.; Huang, X.; Liao, Y.; Hu, Z.; Luo, M. miR-484/MAP2/c-Myc-positive regulatory loop in glioma promotes tumor-initiating properties through ERK1/2 signaling. J. Mol. Histol. 2018, 49, 209–218. [Google Scholar] [CrossRef] [PubMed]
  186. Li, T.; Ding, Z.L.; Zheng, Y.L.; Wang, W. MiR-484 promotes non-small-cell lung cancer (NSCLC) progression through inhibiting Apaf-1 associated with the suppression of apoptosis. Biomed. Pharm. 2017, 96, 153–164. [Google Scholar] [CrossRef] [PubMed]
  187. Wang, K.; Long, B.; Jiao, J.Q.; Wang, J.X.; Liu, J.P.; Li, Q.; Li, P.F. miR-484 regulates mitochondrial network through targeting Fis1. Nat. Commun. 2012, 3, 781. [Google Scholar] [CrossRef]
  188. Lu, X.; Lu, J. The significance of detection of serum miR-423-5p and miR-484 for diagnosis of colorectal cancer. Clin. Lab. 2015, 61, 187–190. [Google Scholar] [CrossRef]
  189. Merhautova, J.; Hezova, R.; Poprach, A.; Kovarikova, A.; Radova, L.; Svoboda, M.; Vyzula, R.; Demlova, R.; Slaby, O. miR-155 and miR-484 are associated with time to progression in metastatic renal cell carcinoma treated with sunitinib. Biomed. Res. Int. 2015, 2015, 941980. [Google Scholar] [CrossRef] [Green Version]
  190. Ye, F.G.; Song, C.G.; Cao, Z.G.; Xia, C.; Chen, D.N.; Chen, L.; Li, S.; Qiao, F.; Ling, H.; Yao, L. Cytidine deaminase axis modulated by miR-484 differentially regulates cell proliferation and chemoresistance in breast cancer. Cancer Res. 2015, 75, 1504–1515. [Google Scholar] [CrossRef] [Green Version]
  191. Wang, R.; Bao, H.; Zhang, S.; Li, R.; Chen, L.; Zhu, Y. miR-186-5p promotes apoptosis by targeting IGF-1 in SH-SY5Y OGD/R model. Int. J. Biol. Sci. 2018, 14, 1791–1799. [Google Scholar] [CrossRef]
  192. Silva, M.M.; Rodrigues, B.; Fernandes, J.; Santos, S.D.; Carreto, L.; Santos, M.A.S.; Pinheiro, P.; Carvalho, A.L. MicroRNA-186-5p controls GluA2 surface expression and synaptic scaling in hippocampal neurons. Proc. Natl. Acad. Sci. USA 2019, 116, 5727–5736. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  193. Li, Z.; Wu, J.; Wei, W.; Cai, X.; Yan, J.; Song, J.; Wang, C.; Wang, J. Association of serum miR-186-5p with the prognosis of acute coronary syndrome patients after percutaneous coronary intervention. Front. Physiol. 2019, 10, 686. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  194. Han, D.X.; Xiao, Y.; Wang, C.J.; Jiang, H.; Gao, Y.; Yuan, B.; Zhang, J.B. Regulation of FSH expression by differentially expressed miR-186-5p in rat anterior adenohypophyseal cells. PLoS ONE 2018, 13, e0194300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  195. Zhang, Z.; Zhang, W.; Mao, J.; Xu, Z.; Fan, M. miR-186-5p functions as a tumor suppressor in human osteosarcoma by targeting FOXK1. Cell. Physiol. Biochem. 2019, 52, 553–564. [Google Scholar]
  196. Cao, Q.; Wang, Z.; Wang, Y.; Liu, F.; Dong, Y.; Zhang, W.; Wang, L.; Ke, Z. TBL1XR1 promotes migration and invasion in osteosarcoma cells and is negatively regulated by miR-186-5p. Am. J. Cancer Res. 2018, 8, 2481–2493. [Google Scholar]
  197. Li, J.; Xia, L.; Zhou, Z.; Zuo, Z.; Xu, C.; Song, H.; Cai, J. MiR-186-5p upregulation inhibits proliferation, metastasis and epithelial-to-mesenchymal transition of colorectal cancer cell by targeting ZEB1. Arch. Biochem. Biophys. 2018, 640, 53–60. [Google Scholar] [CrossRef]
  198. Zhu, K.; Su, Y.; Xu, B.; Wang, Z.; Sun, H.; Wang, L.; Sun, C.; He, X. MicroRNA-186-5p represses neuroblastoma cell growth via downregulation of Eg5. Am. J. Transl. Res. 2019, 11, 2245–2256. [Google Scholar]
  199. Feng, H.; Zhang, Z.; Qing, X.; French, S.W.; Liu, D. miR-186-5p promotes cell growth, migration and invasion of lung adenocarcinoma by targeting PTEN. Exp. Mol. Pathol. 2019, 108, 105–113. [Google Scholar] [CrossRef]
  200. Jones, D.Z.; Schmidt, M.L.; Suman, S.; Hobbing, K.R.; Barve, S.S.; Gobejishvili, L.; Brock, G.; Klinge, C.M.; Rai, S.N.; Park, J.; et al. Micro-RNA-186-5p inhibition attenuates proliferation, anchorage independent growth and invasion in metastatic prostate cancer cells. BMC Cancer 2018, 18, 421. [Google Scholar] [CrossRef] [Green Version]
  201. Zhang, Z.; Li, X.; Sun, W.; Yue, S.; Yang, J.; Li, J.; Ma, B.; Wang, J.; Yang, X.; Pu, M.; et al. Loss of exosomal miR-320a from cancer-associated fibroblasts contributes to HCC proliferation and metastasis. Cancer Lett. 2017, 397, 33–42. [Google Scholar] [CrossRef]
  202. Lv, G.; Wu, M.; Wang, M.; Jiang, X.; Du, J.; Zhang, K.; Li, D.; Ma, N.; Peng, Y.; Wang, L.; et al. miR-320a regulates high mobility group box 1 expression and inhibits invasion and metastasis in hepatocellular carcinoma. Liver Int. 2017, 37, 1354–1364. [Google Scholar] [CrossRef] [PubMed]
  203. Zhao, W.; Sun, Q.; Yu, Z.; Mao, S.; Jin, Y.; Li, J.; Jiang, Z.; Zhang, Y.; Chen, M.; Chen, P.; et al. miR-320a-3p/ELF3 axis regulates cell metastasis and invasion in non-small cell lung cancer via PI3K/Akt pathway. Gene 2018, 670, 31–37. [Google Scholar] [CrossRef] [PubMed]
  204. Li, H.; Yu, L.; Liu, J.; Bian, X.; Shi, C.; Sun, C.; Zhou, X.; Wen, Y.; Hua, D.; Zhao, S.; et al. miR-320a functions as a suppressor for gliomas by targeting SND1 and beta-catenin, and predicts the prognosis of patients. Oncotarget 2017, 8, 19723–19737. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  205. Wang, Y.; Zeng, J.; Pan, J.; Geng, X.; Li, L.; Wu, J.; Song, P.; Wang, Y.; Liu, J.; Wang, L. miR-320a inhibits gastric carcinoma by targeting activity in the FoxM1-P27KIP1 axis. Oncotarget 2016, 7, 29275–29786. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  206. Li, Y.; Liu, H.; Shao, J.; Xing, G. miR-320a serves as a negative regulator in the progression of gastric cancer by targeting RAB14. Mol. Med. Rep. 2017, 16, 2652–2658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  207. Lv, Q.; Hu, J.X.; Li, Y.J.; Xie, N.; Song, D.D.; Zhao, W.; Yan, Y.F.; Li, B.S.; Wang, P.Y.; Xie, S.Y. miR-320a effectively suppresses lung adenocarcinoma cell proliferation and metastasis by regulating STAT3 signals. Cancer Biol. 2017, 18, 142–151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  208. Xie, N.; Wang, C.; Zhuang, Z.; Hou, J.; Liu, X.; Wu, Y.; Liu, H.; Huang, H. Decreased miR-320a promotes invasion and metastasis of tumor budding cells in tongue squamous cell carcinoma. Oncotarget 2016, 7, 65744–65757. [Google Scholar] [CrossRef] [Green Version]
  209. Lu, Y.; Wu, D.; Wang, J.; Li, Y.; Chai, X.; Kang, Q. miR-320a regulates cell proliferation and apoptosis in multiple myeloma by targeting pre-B-cell leukemia transcription factor 3. Biochem. Biophys. Res. Commun. 2016, 473, 1315–1320. [Google Scholar] [CrossRef]
  210. Yu, J.; Wang, L.; Yang, H.; Ding, D.; Zhang, L.; Wang, J.; Chen, Q.; Zou, Q.; Jin, Y.; Liu, X. Rab14 suppression mediated by miR-320a inhibits cell proliferation, migration and invasion in breast cancer. J. Cancer 2016, 7, 2317–2326. [Google Scholar] [CrossRef] [Green Version]
  211. Zhao, H.; Zhao, H.; Dong, T.; Zhou, H.; Wang, L.; Huang, A.; Feng, B.; Quan, Y.; Jin, R.; Zhang, W.; et al. miR-320a suppresses colorectal cancer progression by targeting Rac1. Carcinogenesis 2014, 35, 886–895. [Google Scholar] [CrossRef] [Green Version]
  212. Shang, C.; Zhang, H.; Guo, Y.; Hong, Y.; Liu, Y.; Xue, Y. miR-320a down-regulation mediates bladder carcinoma invasion by targeting ITGB3. Mol. Biol. Rep. 2014, 41, 2521–2527. [Google Scholar] [CrossRef] [PubMed]
  213. He, M.; Wang, J.; Yin, Z.; Zhao, Y.; Hou, H.; Fan, J.; Li, H.; Wen, Z.; Tang, J.; Wang, Y.; et al. miR-320a induces diabetic nephropathy via inhibiting MafB. Aging 2019, 11, 3055–3079. [Google Scholar] [CrossRef] [PubMed]
  214. Jin, Y.; Chen, X.; Gao, Z.Y.; Liu, K.; Hou, Y.; Zheng, J. The role of miR-320a and IL-1beta in human chondrocyte degradation. Bone Jt. Res. 2017, 6, 196–203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  215. De-Ugarte, L.; Balcells, S.; Nogues, X.; Grinberg, D.; Diez-Perez, A.; Garcia-Giralt, N. Pro-osteoporotic miR-320a impairs osteoblast function and induces oxidative stress. PLoS ONE 2018, 13, e0208131. [Google Scholar] [CrossRef] [PubMed]
  216. Kong, Y.; Nie, Z.K.; Li, F.; Guo, H.M.; Yang, X.L.; Ding, S.F. miR-320a was highly expressed in postmenopausal osteoporosis and acts as a negative regulator in MC3T3E1 cells by reducing MAP9 and inhibiting PI3K/AKT signaling pathway. Exp. Mol. Pathol. 2019, 110, 104282. [Google Scholar] [CrossRef]
  217. Yin, Z.; Zhao, Y.; Li, H.; Yan, M.; Zhou, L.; Chen, C.; Wang, D.W. miR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway. Aging 2016, 8, 192–207. [Google Scholar] [CrossRef] [Green Version]
  218. Gao, T.; Deng, M.; Wang, Q. MiRNA-320a inhibits trophoblast cell invasion by targeting estrogen-related receptor-gamma. J. Obs. Gynaecol. Res. 2018, 44, 756–763. [Google Scholar] [CrossRef]
  219. Chen, C.; Wang, Y.; Yang, S.; Li, H.; Zhao, G.; Wang, F.; Yang, L.; Wang, D.W. miR-320a contributes to atherogenesis by augmenting multiple risk factors and down-regulating SRF. J. Cell. Mol. Med. 2015, 19, 970–985. [Google Scholar] [CrossRef]
  220. Sommariva, E.; D’Alessandra, Y.; Farina, F.M.; Casella, M.; Cattaneo, F.; Catto, V.; Chiesa, M.; Stadiotti, I.; Brambilla, S.; Dello Russo, A.; et al. miR-320a as a potential novel circulating biomarker of arrhythmogenic cardiomyopathy. Sci. Rep. 2017, 7, 4802. [Google Scholar] [CrossRef]
  221. Zhang, C.L.; Wang, H.; Yan, C.Y.; Gao, X.F.; Ling, X.J. Deregulation of RUNX2 by miR-320a deficiency impairs steroidogenesis in cumulus granulosa cells from polycystic ovary syndrome (PCOS) patients. Biochem. Biophys. Res. Commun. 2017, 482, 1469–1476. [Google Scholar] [CrossRef]
  222. Zhou, X.; Li, Q.; Xu, J.; Zhang, X.; Zhang, H.; Xiang, Y.; Fang, C.; Wang, T.; Xia, S.; Zhang, Q.; et al. The aberrantly expressed miR-193b-3p contributes to preeclampsia through regulating transforming growth factor-beta signaling. Sci. Rep. 2016, 6, 19910. [Google Scholar] [CrossRef] [PubMed]
  223. Zhang, J.; Qin, J.; Su, Y. miR-193b-3p possesses anti-tumor activity in ovarian carcinoma cells by targeting p21-activated kinase 3. Biomed. Pharm. 2017, 96, 1275–1282. [Google Scholar] [CrossRef] [PubMed]
  224. Yang, Z.; Zhuang, Q.; Hu, G.; Geng, S. MORC4 is a novel breast cancer oncogene regulated by miR-193b-3p. J. Cell. Biochem. 2019, 120, 4634–4643. [Google Scholar] [CrossRef] [PubMed]
  225. Lin, S.R.; Yeh, H.C.; Wang, W.J.; Ke, H.L.; Lin, H.H.; Hsu, W.C.; Chao, S.Y.; Hour, T.C.; Wu, W.J.; Pu, Y.S.; et al. miR-193b mediates CEBPD-induced cisplatin sensitization through targeting ETS1 and cyclin D1 in human urothelial carcinoma cells. J. Cell. Biochem. 2017, 118, 1563–1573. [Google Scholar] [CrossRef] [PubMed]
  226. Ma, W.; Dou, Q.; Ha, X. Let-7a-5p inhibits BMSCs osteogenesis in postmenopausal osteoporosis mice. Biochem. Biophys. Res. Commun. 2019, 510, 53–58. [Google Scholar] [CrossRef] [PubMed]
  227. Li, J.P.; Liao, X.H.; Xiang, Y.; Yao, A.; Song, R.H.; Zhang, Z.J.; Huang, F.; Dai, Z.T.; Zhang, T.C. Hyperoside and let-7a-5p synergistically inhibits lung cancer cell proliferation via inducing G1/S phase arrest. Gene. 2018, 679, 232–240. [Google Scholar] [CrossRef] [PubMed]
  228. Duan, S.; Yu, S.; Yuan, T.; Yao, S.; Zhang, L. Exogenous let-7a-5p induces A549 lung cancer cell death through BCL2L1-mediated PI3Kgamma signaling pathway. Front. Oncol. 2019, 9, 808. [Google Scholar] [CrossRef]
  229. Wu, W.Y.; Tao, S.Q.; Wang, X.N.; Lobie, P.E.; Wu, Z.S. XIAP 3′-untranslated region serves as a competitor for HMGA2 by arresting endogenous let-7a-5p in human hepatocellular carcinoma. Tumour. Biol. 2017, 39, 1010428317719578. [Google Scholar] [CrossRef] [Green Version]
  230. Liu, T.P.; Huang, C.C.; Yeh, K.T.; Ke, T.W.; Wei, P.L.; Yang, J.R.; Cheng, Y.W. Down-regulation of let-7a-5p predicts lymph node metastasis and prognosis in colorectal cancer: Implications for chemotherapy. Surg. Oncol. 2016, 25, 429–434. [Google Scholar] [CrossRef]
  231. Fasihi-Ramandi, M.; Moridnia, A.; Najafi, A.; Sharifi, M. Inducing apoptosis and decreasing cell proliferation in human acute promyelocytic leukemia through regulation expression of CASP3 by let-7a-5p blockage. Indian J. Hematol. Blood Transfus. 2018, 34, 70–77. [Google Scholar] [CrossRef]
  232. Wang, T.; Zhu, H.; Yang, S.; Fei, X. Let-7a-5p may participate in the pathogenesis of diabetic nephropathy through targeting HMGA2. Mol. Med. Rep. 2019, 19, 4229–4237. [Google Scholar] [CrossRef] [PubMed]
  233. Matsuura, K.; Aizawa, N.; Enomoto, H.; Nishiguchi, S.; Toyoda, H.; Kumada, T.; Iio, E.; Ito, K.; Ogawa, S.; Isogawa, M.; et al. Circulating let-7 levels in serum correlate with the severity of hepatic fibrosis in chronic hepatitis C. Open Forum Infect. Dis. 2018, 5, ofy268. [Google Scholar] [CrossRef] [PubMed]
  234. Chen, X.; Luo, H.; Li, X.; Tian, X.; Peng, B.; Liu, S.; Zhan, T.; Wan, Y.; Chen, W.; Li, Y.; et al. miR-331-3p functions as an oncogene by targeting ST7L in pancreatic cancer. Carcinogenesis 2018, 39, 1006–1015. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  235. Jin, W.; Zhong, N.; Wang, L.; Yu, J.; Yin, F.; Zhang, K. miR-331-3p inhibition of the hepatocellular carcinoma (HCC) Bel-7402 cell line by down-regulation of E2F1. J. Nanosci. Nanotechnol. 2019, 19, 5476–5482. [Google Scholar] [CrossRef]
  236. Cao, Y.; Chen, J.; Wang, D.; Peng, H.; Tan, X.; Xiong, D.; Huang, A.; Tang, H. Upregulated in hepatitis B virus-associated hepatocellular carcinoma cells, miR-331-3p promotes proliferation of hepatocellular carcinoma cells by targeting ING5. Oncotarget 2015, 6, 38093–38106. [Google Scholar] [CrossRef] [Green Version]
  237. Sun, Q.; Li, J.; Jin, B.; Wang, T.; Gu, J. Evaluation of miR-331-3p and miR-23b-3p as serum biomarkers for hepatitis c virus-related hepatocellular carcinoma at early stage. Clin. Res. Hepatol. Gastroenterol. 2019, 44, 21–28. [Google Scholar] [CrossRef]
  238. Gu, J.; Zhang, J.; Zheng, L.; Ajani, J.A.; Wu, X.; Ye, Y. Serum miR-331-3p predicts tumor recurrence in esophageal adenocarcinoma. Sci. Rep. 2018, 8, 14006. [Google Scholar] [CrossRef]
  239. Epis, M.R.; Giles, K.M.; Beveridge, D.J.; Richardson, K.L.; Candy, P.A.; Stuart, L.M.; Bentel, J.; Cohen, R.J.; Leedman, P.J. miR-331-3p and aurora kinase inhibitor II co-treatment suppresses prostate cancer tumorigenesis and progression. Oncotarget 2017, 8, 55116–55134. [Google Scholar] [CrossRef] [Green Version]
  240. Epis, M.R.; Giles, K.M.; Barker, A.; Kendrick, T.S.; Leedman, P.J. miR-331-3p regulates ERBB-2 expression and androgen receptor signaling in prostate cancer. J. Biol. Chem. 2009, 284, 24696–24704. [Google Scholar] [CrossRef] [Green Version]
  241. Zhao, D.; Sui, Y.; Zheng, X. miR-331-3p inhibits proliferation and promotes apoptosis by targeting HER2 through the PI3K/Akt and ERK1/2 pathways in colorectal cancer. Oncol. Rep. 2016, 35, 1075–1082. [Google Scholar] [CrossRef] [Green Version]
  242. Li, X.; Zhu, J.; Liu, Y.; Duan, C.; Chang, R.; Zhang, C. MicroRNA-331-3p inhibits epithelial-mesenchymal transition by targeting ErbB2 and VAV2 through the Rac1/PAK1/beta-catenin axis in non-small-cell lung cancer. Cancer Sci. 2019, 110, 1883–1896. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  243. Epis, M.R.; Giles, K.M.; Candy, P.A.; Webster, R.J.; Leedman, P.J. miR-331-3p regulates expression of neuropilin-2 in glioblastoma. J. Neurooncol. 2014, 116, 67–75. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  244. Fujii, T.; Shimada, K.; Asano, A.; Tatsumi, Y.; Yamaguchi, N.; Yamazaki, M.; Konishi, N. MicroRNA-331-3p suppresses cervical cancer cell proliferation and E6/E7 expression by targeting NRP2. Int. J. Mol. Sci. 2016, 17, 1351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  245. Buranjiang, G.; Kuerban, R.; Abuduwanke, A.; Li, X.; Kuerban, G. MicroRNA-331-3p inhibits proliferation and metastasis of ovarian cancer by targeting RCC2. Arch. Med. Sci. 2019, 15, 1520–1529. [Google Scholar] [CrossRef] [PubMed]
  246. Morita, K.; Fujii, T.; Itami, H.; Uchiyama, T.; Nakai, T.; Hatakeyama, K.; Sugimoto, A.; Miyake, M.; Nakai, Y.; Tanaka, N.; et al. NACC1, as a target of microRNA-331-3p, regulates cell proliferation in urothelial carcinoma cells. Cancers 2018, 10, 347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  247. Guo, X.; Guo, L.; Ji, J.; Zhang, J.; Zhang, J.; Chen, X.; Cai, Q.; Li, J.; Gu, Q.; Liu, B.; et al. miRNA-331-3p directly targets E2F1 and induces growth arrest in human gastric cancer. Biochem. Biophys. Res. Commun. 2010, 398, 1–6. [Google Scholar] [CrossRef]
  248. Fan, W.; Liu, Y.; Li, C.; Qu, X.; Zheng, G.; Zhang, Q.; Pan, Z.; Wang, Y.; Rong, J. microRNA-331-3p maintains the contractile type of vascular smooth muscle cells by regulating TNF-alpha and CD14 in intracranial aneurysm. Neuropharmacology 2019, 164, 107858. [Google Scholar] [CrossRef]
  249. Chen, Z.; Li, Z.; Jiang, C.; Jiang, X.; Zhang, J. MiR-92b-3p promotes neurite growth and functional recovery via the PTEN/AKT pathway in acute spinal cord injury. J. Cell. Physiol. 2019, 234, 23043–23052. [Google Scholar] [CrossRef]
  250. Hu, Z.Q.; Luo, J.F.; Yu, X.J.; Zhu, J.N.; Huang, L.; Yang, J.; Fu, Y.H.; Li, T.; Xue, Y.M.; Feng, Y.Q.; et al. Targeting myocyte-specific enhancer factor 2D contributes to the suppression of cardiac hypertrophic growth by miR-92b-3p in mice. Oncotarget 2017, 8, 92079–92089. [Google Scholar] [CrossRef] [Green Version]
  251. Yu, X.J.; Huang, Y.Q.; Shan, Z.X.; Zhu, J.N.; Hu, Z.Q.; Huang, L.; Feng, Y.Q.; Geng, Q.S. MicroRNA-92b-3p suppresses angiotensin II-induced cardiomyocyte hypertrophy via targeting HAND2. Life Sci. 2019, 232, 116635. [Google Scholar] [CrossRef]
  252. Long, M.; Zhan, M.; Xu, S.; Yang, R.; Chen, W.; Zhang, S.; Shi, Y.; He, Q.; Mohan, M.; Liu, Q.; et al. miR-92b-3p acts as a tumor suppressor by targeting Gabra3 in pancreatic cancer. Mol. Cancer 2017, 16, 167. [Google Scholar] [CrossRef] [Green Version]
  253. Gong, L.; Ren, M.; Lv, Z.; Yang, Y.; Wang, Z. miR-92b-3p promotes colorectal carcinoma cell proliferation, invasion, and migration by inhibiting FBXW7 in vitro and in vivo. DNA Cell. Biol. 2018, 37, 501–511. [Google Scholar] [CrossRef] [PubMed]
  254. Wang, W.; Fu, S.; Lin, X.; Zheng, J.; Pu, J.; Gu, Y.; Deng, W.; Liu, Y.; He, Z.; Liang, W.; et al. miR-92b-3p functions as a key gene in esophageal squamous cell cancer as determined by co-expression analysis. Onco. Targets 2019, 12, 8339–8353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  255. Li, C.; Huo, B.; Wang, Y.; Cheng, C. Downregulation of microRNA-92b-3p suppresses proliferation, migration, and invasion of gastric cancer SGC-7901 cells by targeting Homeobox D10. J. Cell. Biochem. 2019, 120, 17405–17412. [Google Scholar] [CrossRef] [PubMed]
  256. Uotani, K.; Fujiwara, T.; Yoshida, A.; Iwata, S.; Morita, T.; Kiyono, M.; Yokoo, S.; Kunisada, T.; Takeda, K.; Hasei, J.; et al. Circulating microRNA-92b-3p as a novel biomarker for monitoring of synovial sarcoma. Sci. Rep. 2017, 7, 14634. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  257. Jiang, Q.; Lu, X.; Huang, P.; Gao, C.; Zhao, X.; Xing, T.; Li, G.; Bao, S.; Zheng, H. Expression of miR-652-3p and effect on apoptosis and drug sensitivity in pediatric acute lymphoblastic leukemia. Biomed. Res. Int. 2018, 2018, 5724686. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  258. Zhu, Q.L.; Zhan, D.M.; Chong, Y.K.; Ding, L.; Yang, Y.G. miR-652-3p promotes bladder cancer migration and invasion by targeting KCNN3. Eur. Rev. Med. Pharm. Sci. 2019, 23, 8806–8812. [Google Scholar]
  259. Yang, W.; Zhou, C.; Luo, M.; Shi, X.; Li, Y.; Sun, Z.; Zhou, F.; Chen, Z.; He, J. miR-652-3p is upregulated in non-small cell lung cancer and promotes proliferation and metastasis by directly targeting Lgl1. Oncotarget 2016, 7, 16703–16715. [Google Scholar] [CrossRef] [Green Version]
  260. Nam, R.K.; Benatar, T.; Amemiya, Y.; Wallis, C.J.D.; Romero, J.M.; Tsagaris, M.; Sherman, C.; Sugar, L.; Seth, A. MicroRNA-652 induces NED in LNCaP and EMT in PC3 prostate cancer cells. Oncotarget 2018, 9, 19159–19176. [Google Scholar] [CrossRef] [Green Version]
  261. Huang, R.; Hu, Z.; Cao, Y.; Li, H.; Zhang, H.; Su, W.; Xu, Y.; Liang, L.; Melgiri, N.D.; Jiang, L. miR-652-3p inhibition enhances endothelial repair and reduces atherosclerosis by promoting Cyclin D2 expression. EBioMedicine 2019, 40, 685–694. [Google Scholar] [CrossRef] [Green Version]
  262. You, Y.; Que, K.; Zhou, Y.; Zhang, Z.; Zhao, X.; Gong, J.; Liu, Z. MicroRNA-766-3p inhibits tumour progression by targeting Wnt3a in hepatocellular carcinoma. Mol. Cells 2018, 41, 830–841. [Google Scholar] [PubMed]
  263. Chen, C.; Xue, S.; Zhang, J.; Chen, W.; Gong, D.; Zheng, J.; Ma, J.; Xue, W.; Chen, Y.; Zhai, W.; et al. DNA-methylation-mediated repression of miR-766-3p promotes cell proliferation via targeting SF2 expression in renal cell carcinoma. Int. J. Cancer 2017, 141, 1867–1878. [Google Scholar] [CrossRef] [PubMed]
  264. Kleemann, M.; Schneider, H.; Unger, K.; Sander, P.; Schneider, E.M.; Fischer-Posovszky, P.; Handrick, R.; Otte, K. miR-744-5p inducing cell death by directly targeting HNRNPC and NFIX in ovarian cancer cells. Sci. Rep. 2018, 8, 9020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  265. Chen, S.; Shi, F.; Zhang, W.; Zhou, Y.; Huang, J. miR-744-5p inhibits non-small cell lung cancer proliferation and invasion by directly targeting PAX2. Technol. Cancer Res. Treat. 2019, 18, 1533033819876913. [Google Scholar] [CrossRef] [Green Version]
  266. Cai, B.; Ma, M.; Chen, B.; Li, Z.; Abdalla, B.A.; Nie, Q.; Zhang, X. MiR-16-5p targets SESN1 to regulate the p53 signaling pathway, affecting myoblast proliferation and apoptosis, and is involved in myoblast differentiation. Cell Death Dis. 2018, 9, 367. [Google Scholar] [CrossRef] [Green Version]
  267. Liu, G.P.; Wang, W.W.; Lu, W.Y.; Shang, A.Q. The mechanism of miR-16-5p protection on LPS-induced A549 cell injury by targeting CXCR3. Artif. Cells Nanomed. Biotechnol. 2019, 47, 1200–1206. [Google Scholar] [CrossRef] [Green Version]
  268. Cun, J.; Yang, Q. Bioinformatics-based interaction analysis of miR-92a-3p and key genes in tamoxifen-resistant breast cancer cells. Biomed. Pharm. 2018, 107, 117–128. [Google Scholar] [CrossRef]
  269. Yin, J.; Zhuang, G.; Zhu, Y.; Hu, X.; Zhao, H.; Zhang, R.; Guo, H.; Fan, X.; Cao, Y. MiR-615-3p inhibits the osteogenic differentiation of human lumbar ligamentum flavum cells via suppression of osteogenic regulators GDF5 and FOXO1. Cell. Biol. Int. 2017, 41, 779–786. [Google Scholar] [CrossRef]
  270. Yan, T.; Ooi, W.F.; Qamra, A.; Cheung, A.; Ma, D.; Sundaram, G.M.; Xu, C.; Xing, M.; Poon, L.; Wang, J.; et al. HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis. Nat. Commun. 2018, 9, 100. [Google Scholar] [CrossRef]
  271. Miyamoto, Y.; Mauer, A.S.; Kumar, S.; Mott, J.L.; Malhi, H. Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. PLoS ONE 2014, 9, e109637. [Google Scholar] [CrossRef]
  272. Zhuang, Z.; Sun, C.; Gong, H. High serum miR-484 expression is associated with the diagnosis and prognosis of patients with non-small cell lung cancer. Exp. Med. 2019, 18, 4095–4102. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  273. Fujitani, M.; Fujitani, M.; Zhang, S.; Fujiki, R.; Fujihara, Y.; Yamashita, T. A chromosome 16p13.11 microduplication causes hyperactivity through dysregulation of miR-484/protocadherin-19 signaling. Mol. Psychiatry 2017, 22, 364–374. [Google Scholar] [PubMed]
  274. Liu, H.; Li, S.; Jiang, W.; Li, Y. miR-484 protects rat myocardial cells from ischemia-reperfusion injury by inhibiting caspase-3 and caspase-9 during apoptosis. Korean Circ. J. 2019, 50, 250–263. [Google Scholar] [CrossRef] [PubMed]
  275. Jiang, J.; Mo, H.; Liu, C.; Wu, B.; Wu, Z.; Li, X.; Li, T.; He, S.; Li, S.; You, Q. Inhibition of miR-186-5p contributes to high glucose-induced injury in AC16 cardiomyocytes. Exp. Med. 2018, 15, 627–632. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  276. Liu, Y.; Zheng, W.; Pan, Y.; Hu, J. Low expression of miR-186-5p regulates cell apoptosis by targeting toll-like receptor 3 in high glucose-induced cardiomyocytes. J. Cell. Biochem. 2019, 120, 9532–9538. [Google Scholar] [CrossRef]
  277. Meng, F.; Li, Z.; Zhang, Z.; Yang, Z.; Kang, Y.; Zhao, X.; Long, D.; Hu, S.; Gu, M.; He, S.; et al. microRNA-193b-3p regulates chondrogenesis and chondrocyte metabolism by targeting HDAC3. Theranostics 2018, 8, 2862–2883. [Google Scholar] [CrossRef]
  278. Chang, Z.K.; Meng, F.G.; Zhang, Z.Q.; Mao, G.P.; Huang, Z.Y.; Liao, W.M.; He, A.S. microRNA-193b-3p regulates matrix metalloproteinase 19 expression in interleukin-1beta-induced human chondrocytes. J. Cell. Biochem. 2018, 119, 4775–4782. [Google Scholar] [CrossRef]
  279. Chen, X.; Zhang, R.; Zhang, Q.; Xu, Z.; Xu, F.; Li, D.; Li, Y. Chondrocyte sheet in vivo cartilage regeneration technique using miR-193b-3p to target MMP16. Aging 2019, 11, 7070–7082. [Google Scholar] [CrossRef]
  280. Xu, L.; Cao, H.; Xie, Y.; Zhang, Y.; Du, M.; Xu, X.; Ye, R.; Liu, X. Exosome-shuttled miR-92b-3p from ischemic preconditioned astrocytes protects neurons against oxygen and glucose deprivation. Brain Res. 2019, 1717, 66–73. [Google Scholar] [CrossRef]
  281. Hao, X.; Ma, C.; Chen, S.; Dang, J.; Cheng, X.; Zhu, D. Reverse the down regulation of miR-92b-3p by hypoxia can suppress the proliferation of pulmonary artery smooth muscle cells by targeting USP28. Biochem. Biophys. Res. Commun. 2018, 503, 3064–3077. [Google Scholar] [CrossRef]
  282. Li, T.; Liu, X.; Gong, X.; E, Q.; Zhang, X.; Zhang, X. microRNA 92b-3p regulates primordial follicle assembly by targeting TSC1 in neonatal mouse ovaries. Cell. Cycle 2019, 18, 824–833. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  283. Shi, Z.; Liu, B.; Li, Y.; Liu, F.; Yuan, X.; Wang, Y. MicroRNA-652-3p promotes the proliferation and invasion of the trophoblast HTR-8/SVneo cell line by targeting homeobox A9 to modulate the expression of ephrin receptor B4. Clin. Exp. Pharm. Physiol. 2019, 46, 587–596. [Google Scholar] [CrossRef] [PubMed]
  284. Liu, L.; Qi, X.; Gui, Y.; Huo, H.; Yang, X.; Yang, L. Overexpression of circ_0021093 circular RNA forecasts an unfavorable prognosis and facilitates cell progression by targeting the miR-766-3p/MTA3 pathway in hepatocellular carcinoma. Gene 2019, 714, 143992. [Google Scholar] [CrossRef] [PubMed]
  285. Hayakawa, K.; Kawasaki, M.; Hirai, T.; Yoshida, Y.; Tsushima, H.; Fujishiro, M.; Ikeda, K.; Morimoto, S.; Takamori, K.; Sekigawa, I. MicroRNA-766-3p contributes to anti-inflammatory responses through the indirect inhibition of NF-κB signaling. Int. J. Mol. Sci. 2019, 20, 809. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Cells 10 00110 g001 550
Figure 1. Alteration status of ribosomal proteins (RPs) in cancers and its correlation with patient’s survival status. (a) Bar diagram showing the copy number alteration status of RPs in different types of cancers, the data obtained by analyzing 10,967 samples from “TCGA PanCancer Atlas Studies (32 categories)”, it showed that all of the 32 cancer types have altered the expression of RPs, while ovarian cancer, uterine cancer and esophagus are the top three types of cancer, of which more than 60% samples have alteration of RPs. (b) Survival graph showing that altered expression of RPs are negatively correlated with the survival status of cancer patients. All data were generated using the cBioPortal for Cancer Genomics (http://www.cbioportal.org/index.do) database from the cancer genome atlas (TCGA) Research Network (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga).
Figure 1. Alteration status of ribosomal proteins (RPs) in cancers and its correlation with patient’s survival status. (a) Bar diagram showing the copy number alteration status of RPs in different types of cancers, the data obtained by analyzing 10,967 samples from “TCGA PanCancer Atlas Studies (32 categories)”, it showed that all of the 32 cancer types have altered the expression of RPs, while ovarian cancer, uterine cancer and esophagus are the top three types of cancer, of which more than 60% samples have alteration of RPs. (b) Survival graph showing that altered expression of RPs are negatively correlated with the survival status of cancer patients. All data were generated using the cBioPortal for Cancer Genomics (http://www.cbioportal.org/index.do) database from the cancer genome atlas (TCGA) Research Network (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga).
Cells 10 00110 g001
Cells 10 00110 g002 550
Figure 2. Potential mechanism of microRNA (miRNA) mediated regulation of global protein synthesis. (a) Cell-cell and cell-stromal crosstalk: the transportation of the cell secreted miRNAs and proteins by the extracellular vesicles (exosomes, microparticle and exophers) and lipoproteins to the circulatory system, which carries them further to the neighboring cells and the distant organs. (b) Deregulated expression of miRNAs might cause an imbalance in the expression of ribosomal proteins (RPs) followed by the abnormal assembly of the protein translation machinery (ribosomes); therefore, the ultimate outcome would be the deregulation of the global protein synthesis.
Figure 2. Potential mechanism of microRNA (miRNA) mediated regulation of global protein synthesis. (a) Cell-cell and cell-stromal crosstalk: the transportation of the cell secreted miRNAs and proteins by the extracellular vesicles (exosomes, microparticle and exophers) and lipoproteins to the circulatory system, which carries them further to the neighboring cells and the distant organs. (b) Deregulated expression of miRNAs might cause an imbalance in the expression of ribosomal proteins (RPs) followed by the abnormal assembly of the protein translation machinery (ribosomes); therefore, the ultimate outcome would be the deregulation of the global protein synthesis.
Cells 10 00110 g002
Cells 10 00110 g003 550
Figure 3. Interaction network between ribosomal proteins (RPs) and microRNAs (miRNAs). (a) Top 15 RPs are grouped based on their number of connections to the miRNAs (RPL41, RPL14, RPL18A, RPS15A, RPL13A, RPL24, RPS24, RPL37, RPS16, RPL12, RPS27A, RPS19, RPL27A, RPL23A, and RPLP0, respectively), and these 15 RPs are predicted to be connected by 670 miRNAs. (b) Top 14 miRNAs are grouped based on their number of connections with the RPs (hsa-mir-16-5p, hsa-mir-92a-3p, hsa-mir-100-5p, hsa-mir-615-3p, hsa-mir-484, hsa-mir-186-5p, hsa-mir-320a, hsa-mir-193b-3p, hsa-let-7a-5p, hsa-mir-331-3p, hsa-mir-92b-3p, hsa-mir-652-3p, hsa-mir-766-3p, and hsa-mir-744-5p, respectively), and these 14 miRNAs are potentially connected with 66 RPs. The size of the nodes indicates the degree of connectivity; the bigger the node size, the higher the connection. The interaction network was generated using the miRNet database (https://www.mirnet.ca/).
Figure 3. Interaction network between ribosomal proteins (RPs) and microRNAs (miRNAs). (a) Top 15 RPs are grouped based on their number of connections to the miRNAs (RPL41, RPL14, RPL18A, RPS15A, RPL13A, RPL24, RPS24, RPL37, RPS16, RPL12, RPS27A, RPS19, RPL27A, RPL23A, and RPLP0, respectively), and these 15 RPs are predicted to be connected by 670 miRNAs. (b) Top 14 miRNAs are grouped based on their number of connections with the RPs (hsa-mir-16-5p, hsa-mir-92a-3p, hsa-mir-100-5p, hsa-mir-615-3p, hsa-mir-484, hsa-mir-186-5p, hsa-mir-320a, hsa-mir-193b-3p, hsa-let-7a-5p, hsa-mir-331-3p, hsa-mir-92b-3p, hsa-mir-652-3p, hsa-mir-766-3p, and hsa-mir-744-5p, respectively), and these 14 miRNAs are potentially connected with 66 RPs. The size of the nodes indicates the degree of connectivity; the bigger the node size, the higher the connection. The interaction network was generated using the miRNet database (https://www.mirnet.ca/).
Cells 10 00110 g003
Table
Table 1. Clustering of the human Ribosomal proteins (RPs) according to their involvement in the biological processes.
Table 1. Clustering of the human Ribosomal proteins (RPs) according to their involvement in the biological processes.
Biological ProcessesRibosomal Proteins (RPs) Involved
1. SRP-dependent cotranslational protein targeting to membrane (GO:0006614)RPL4, RPL5, RPL30, RPL3, RPL32, RPL31, RPL34, RPLP1, RPLP0, RPL10A, RPL8, RPL9, RPL6, RPL7, RPS4X, RPS15, RPS14, RPL7A, RPS17, RPS16, RPS19, RPL18A, RPS18, RPL36, RPLP2, RPL35, RPL37, RPS11, RPL39, RPS10, RPS13, RPS12, RPS9, RPL21, RPS7, RPS8, RPL23, RPS5, RPL22, RPS6, RPL13A, RPS3A, RPSA, RPL24, RPL27, RPL26, UBA52, RPL10, RPL12, RPL36A, RPS4Y1, RPS15A, RPS3, RPL14, RPS2, RPL15, RPS27A, RPL18, RPL17, RPL19, RPL41, RPL23A, RPS26, RPS25, RPS28, RPS27, RPS29, RPL27A, RPS20, FAU, RPS21, RPS24, RPS23
2. Viral transcription (GO:0019083)
3. Nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184)
4. Translational initiation (GO:0006413)
5. rRNA processing (GO:0006364)
6. Translation (GO:0006412)
7. Cytoplasmic translation (GO:0002181)RPL31, RPLP1, RPL22, RPLP0, RPL36A, RPL8, RPL9, RPL6, RPL7, RPL36, RPLP2, RPL26, RPL15
8. Ribosomal small subunit assembly (GO:0000028)RPS15, RPS14, RPS17, RPS28, RPS27, RPS19, RPS5, RPSA, RPS10
9. Ribosomal small subunit biogenesis (GO:0042274)RPS15, RPS17, RPS28, RPS16, RPS7, RPS19, RPS6, RPS24
10. Ribosomal large subunit assembly (GO:0000027)RPL5, RPL3, RPL10, RPL12, RPL24, RPL23A, RPL6
11. Maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) (GO:0000462)RPS14, RPS16, RPS19, RPS8, RPS24
12. Ribosome biogenesis (GO:0042254)RPL7A, RPS28, RPS18, RPL34, RPLP0
13. Cell-cell adhesion (GO:0098609)RPS26, RPL7A, RPL34, RPL14, RPL24, RPL23A, RPL15, RPS2, RPL6
14. Ribosomal large subunit biogenesis (GO:0042273)RPL5, RPL14, RPL26, RPL7
15. Liver regeneration (GO:0097421)RPS16, RPL32, RPS24, RPL19
16. Maturation of SSU-rRNA (GO:0030490)RPS14, RPS28, RPS19
17. Endonucleolytic cleavage to generate mature 3′-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) (GO:0000461)RPSA, RPS21
18. DNA damage response, detection of DNA damage (GO:0042769)RPS3, RPS27A, UBA52
19. Negative regulation of RNA splicing (GO:0033119)RPS26, RPS13
20. Endonucleolytic cleavage in ITS1 to separate SSU-rRNA from 5.8S rRNA and LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) (GO:0000447)RPSA, RPS21
21. Maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) (GO:0000463)RPL35, RPL7
22. Erythrocyte homeostasis (GO:0034101)RPS17, RPS24
23. Regulation of necrotic cell death (GO:0010939)RPS27A, UBA52
24. Virion assembly (GO:0019068)RPS27A, UBA52
25. Regulation of type I interferon production (GO:0032479)RPS27A, UBA52
26. MyD88-independent toll-like receptor signaling pathway (GO:0002756)RPS27A, UBA52
27. Maturation of LSU-rRNA (GO:0000470)RPL7A, RPL10A
28. Translational elongation (GO:0006414)RPLP1, RPLP2
29. Response to ethanol (GO:0045471)RPS4X, RPL15, RPL10A
30. Error-free translesion synthesis (GO:0070987)RPS27A, UBA52
31. Error-prone translesion synthesis (GO:0042276)RPS27A, UBA52
32. Stress-activated MAPK cascade (GO:0051403)RPS27A, UBA52
33. Notch signaling pathway (GO:0007219)RPS19, RPS27A, UBA52
34. Nucleotide-excision repair, DNA duplex unwinding (GO:0000717)RPS27A, UBA52
35. Nucleotide-excision repair, DNA damage recognition (GO:0000715)RPS27A, UBA52
36. Positive regulation of epidermal growth factor receptor signaling pathway (GO:0045742)RPS27A, UBA52
37. Nucleotide-excision repair, DNA gap filling (GO:0006297)RPS27A, UBA52
38. Cellular response to interleukin-4 (GO:0071353)RPL3, RPLP0
Table
Table 2. Ribosomal proteins on the biogenesis and assembly of ribosomes, and translation of proteins.
Table 2. Ribosomal proteins on the biogenesis and assembly of ribosomes, and translation of proteins.
Ribosomal ProteinsFunctionsReferences
RPL33Regulates the processing of the 35S and 27S pre-rRNAs[28]
RPS20Regulates mRNA binding and subunits association, mutation impairs 70S subunit formation and mRNA binding to the 30S subunit[30]
RPL16Assembly of 60S subunits[31,52]
RP59Assembly of the 40S subunit[31]
RPL1Maintain the stability of 5S rRNA and assembly of 60S subunits[32,33]
RPL9Maturation of the small subunit[34]
RPL23Chaperone-assisted folding of proteins[37]
RPL35Recognition of peptide and insertion to the translocation channel[38]
RPS12Mutations at lysine-42 of S12, increase accuracy of translation[41]
RPS4Mutation reduces the accuracy of translation[41,43]
RPS5Mutation reduces the accuracy of translation[41]
RPS9Maintain the accuracy of translation[42]
RPS28Maintain the accuracy of translation[43]
RPL39Maintain the accuracy of translation[61]
RPL3Regulates the peptidyltransferase activity and mutation alter the fidelity of translation[45]
RPL5Regulates the peptidyltransferase by helping the anchor of peptidyl-tRNA to the P-site[47]
RPL41Optimizes peptidyltransferase activity by regulating the translocation[46]
RPL24Regulates the P-site binding and kinetics of the protein synthesis[61]
RPL10Regulates nuclear exporting by interacting and releasing cytoplasmic Nmd3p from 60S subunit[48,49,50]
RPL12Assembly of ribosomal stalk[51]
RPS14Maturation of 43S preribosomes[53]
RPS020S rRNA-precursor to mature 18S rRNA[54,55]
RPS21Maturation of the 3′ end of 18S rRNA[55]
RPL25Pre-rRNA processing[56]
RPS15Regulates the nuclear exit of the 40S subunit precursors[57]
Table
Table 3. Involvement of ribosomal proteins in different diseases.
Table 3. Involvement of ribosomal proteins in different diseases.
Major Ribosome Related DiseasesGene InvolvedReference
Diamond–Blackfan anemia (DBA)RPS19, RPS26, RPL5, RPL11[70,71,72]
5q-syndromeRPS14[73]
Schwachman-Diamond syndrome (SDS)SBDS[74]
X-linked dyskeratosis congenita (DC)DKC1[75]
Cartilage hair hypoplasia (CHH)RMRP[76]
Treacher Collins syndrome (TCS)TCOF1[77]
Bowen–Conradi syndrome (BCS)EMG1[78,79,80]
North American Indian childhood cirrhosis (NAIC)CIRH1A[81,82]
Non-small cell lung cancerRPS6, RPS15A[83,84]
Ovarian cancerRPS4X[85]
Bladder cancerRPS4X[86]
Prostate cancerRPL31[87]
Esophageal cancerRPL34[88]
T-cell lymphomaRPL22[89]
Colorectal cancerRPS20[90]
Table
Table 4. The top 14 miRNAs that are predicted to target most of the ribosomal proteins (RPs), along with their reported association to the diseases.
Table 4. The top 14 miRNAs that are predicted to target most of the ribosomal proteins (RPs), along with their reported association to the diseases.
miRNAPredicted Target Ribosomal ProteinsReported Disease Association
hsa-mir-16-5pRPSA, RPL4, RPL9, RPL30, RPS3A, RPS15A, RPS24, RPL12, RPL3, RPL31, RPS6, RPL10, RPL27A, RPLP2, RPS27, RPS5, RPL14, RPL36, RPL5, RPL6, RPL21, RPLP0, RPLP1, RPS2, RPS3, RPS12, RPS17, RPS25, RPS14, RPL19, RPL15, RPL35, RPS19, RPS11breast cancer [147,148], hepatocellular carcinoma (HCC) [149], mesothelioma [150], glioma [151], neuroblastoma [152], chordoma, gastric cancer and osteoarthritis [153,154,155], osteoclastogenesis [156], and rheumatoid arthritis [157].
hsa-mir-92a-3pRPL9, RPL30, RPS3A, RPS10, RPS15A, RPS24, RPL18A, RPL3, RPL27A, RPS5, RPLP1, RPS25, RPL37, RPL7A, RPL24, FAU, RPS14, RPS28, RPL23, RPL13A, RPL39, RPL22, RPS23, RPL8, RPL15, RPL27, RPS8, RPS15melanoma [158], liposarcoma [159], glioma [160], leukemia [161], colorectal cancer [162,163], degradation of cartilage [164], Kawasaki disease [165], schizophrenia [166], systemic lupus erythematosus [167], and white matter impairment and post-stroke depression [168].
hsa-mir-100-5pRPS15A, RPL12, RPL31, RPL10, RPS27, RPL14, RPL5, RPL21, RPLP1, RPS2, RPL7, RPL36A, RPL7A, RPL26, RPL19, RPL15, RPS8, RPS15, RPL10Aprostate cancer [169], RCC [170], oral cancer [171], NSCLC [172], HCC [173], abeta-induced pathologies [174], and hidradenitis suppurativa [175].
hsa-mir-615-3pRPSA, RPL9, RPL3, UBA52, RPL31, RPL36, RPL5, RPL21, RPLP1, RPS2, RPS3, RPS12, RPS17, RPL7, RPL7A, RPL23, RPL15, RPS15gastric cancer [176], prostate cancer [177], NSCLC [178,179], esophageal cancer [180], and HCC [181].
hsa-mir-484RPSA, RPS10, RPS24, RPL3, UBA52, RPL27A, RPLP2, RPL36, RPL5, RPL21, RPLP0, RPLP1, RPS3, FAU, RPS14, RPL13A, RPS18, RPS23, RPS15, RPS29, RPS9, RPL23Acervical cancer [182,183], gastric cancer [184], glioma [185], NSCLC [186], adrenocortical cancer [187], colorectal cancer [188], renal carcinoma [189], and breast cancer [190].
hsa-mir-186-5pRPL4, RPL9, RPS4X, RPL18A, RPL3, RPL14, RPL36, RPL5, RPLP0, RPLP1, RPS2, RPS3, RPS7, RPS26, RPL15, RPL27, RPS29, RPL32, RPS21ischemia stroke [191], hippocampal neurons [192], acute coronary syndrome [193], reproductive health [194], osteosarcoma [195,196], colorectal cancer [197], NSCLC and neuroblastoma [198], lung adenocarcinoma [199], and prostate cancer [200].
hsa-mir-320aRPL9, RPL30, RPS4X, UBA52, RPL10, RPS27, RPL36, RPLP1, RPS2, RPS12, RPS17, RPS16, RPL7A, RPL13A, RPL8, RPL15, RPL27HCC [201,202], NSCLC [203], gliomas [204], gastric cancer [205,206], lung adenocarcinoma [207], tongue squamous cell carcinoma [208], multiple myeloma [209], breast cancer [210], colorectal cancer [211], bladder carcinoma [212], diabetic nephropathy [213], cartilage degradation [214], osteoporosis [215,216], cardiotoxicity [217], anomalous placentation [218], atherogenesis [219], arrhythmogenic cardiomyopathy [220], and polycystic ovary syndrome [221].
hsa-mir-193b-3pRPL9, RPS10, RPL12, RPS6, RPL27A, RPL6, RPLP0, RPS3, FAU, RPL26, RPS18, RPL22, RPL8, RPS21, RPL23Apreeclampsia [222], ovarian cancer [223], breast cancer [224], and urothelial cancer [225].
hsa-let-7a-5pRPSA, RPL4, RPL9, RPL30, RPS3A, RPS4X, RPS10, RPS13, RPS15A, RPS24, RPL31, RPS27, RPLP1, RPS14, RPL8, RPS29osteogenesis [226], lung cancer [227,228], HCC [229], colorectal cancer [230], leukemia cells [231], diabetic nephropathy [232], hepatic fibrosis [233].
hsa-mir-331-3pRPS4Y1, RPS27, RPLP0, RPLP1, RPS2, RPS3, RPS12, RPL36A, RPL7A, RPS14, RPL13A, RPS29, RPS9, RPL34pancreatic cancer [234], HCC [235,236,237], esophageal adenocarcinoma [238], prostate cancer [239,240], colorectal cancer [241], NSCLC [242], glioblastoma and cervical cancer [243,244], ovarian cancer [245], urothelial cancer [246], and gastric cancer [247], intracranial aneurysm [248].
hsa-mir-92b-3pRPL9, RPL30, RPS3A, RPS4X, RPL3, RPLP0, RPL37, RPL24, RPS14, RPS28, RPL23, RPL8acute spinal cord injury [249], cardiac hypertrophy [250,251], pancreatic cancer [252], colorectal cancer [253], esophageal squamous cell carcinoma [254], gastric cancer [255], and synovial sarcoma [256].
hsa-mir-652-3pRPL4, RPL18, RPL18A, RPS6, RPL21, RPLP1, RPS12, RPS16, RPL26, RPL19, RPS23, RPL27, RPS29, RPL32, RPS19lymphoblastic leukemia [257], bladder cancer [258], NSCLC [259], prostate cancer [260], and atherosclerosis [261].
hsa-mir-766-3pRPS15A, RPL12, UBA52, RPL27A, RPLP2, RPL23, RPS26, RPL27, RPS9, RPS19, RPS21HCC [262], and RCC [263].
hsa-mir-744-5pRPL4, RPL18, RPL18A, RPL3, RPS6, RPL10, RPL36, RPLP1, RPL37, RPL7A, RPS14ovarian cancer [264], and NSCLC [265].
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Reza, A.M.M.T.; Yuan, Y.-G. microRNAs Mediated Regulation of the Ribosomal Proteins and its Consequences on the Global Translation of Proteins. Cells 2021, 10, 110. https://doi.org/10.3390/cells10010110

AMA Style

Reza AMMT, Yuan Y-G. microRNAs Mediated Regulation of the Ribosomal Proteins and its Consequences on the Global Translation of Proteins. Cells. 2021; 10(1):110. https://doi.org/10.3390/cells10010110

Chicago/Turabian Style

Reza, Abu Musa Md Talimur, and Yu-Guo Yuan. 2021. "microRNAs Mediated Regulation of the Ribosomal Proteins and its Consequences on the Global Translation of Proteins" Cells 10, no. 1: 110. https://doi.org/10.3390/cells10010110

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop