Next Article in Journal
The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma
Next Article in Special Issue
Salivary Biomarkers in Patients with Sjögren’s Syndrome—A Systematic Review
Previous Article in Journal
Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
Previous Article in Special Issue
Salivary Cytokines as Biomarkers for Oral Squamous Cell Carcinoma: A Systematic Review
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 22
Issue 22
10.3390/ijms222212215
ijms-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

Role of Salivary MicroRNA and Cytokines in the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma

by
Francisco Javier Manzano-Moreno
1,2,
Victor J. Costela-Ruiz
2,3,
Enrique García-Recio
2,4,
Maria Victoria Olmedo-Gaya
5,
Concepción Ruiz
2,6,7,* and
Candelaria Reyes-Botella
1,2
1
Biomedical Group (BIO277), Department of Stomatology, School of Dentistry, University of Granada, 18071 Granada, Spain
2
Instituto Investigación Biosanitaria, ibs.Granada, 18071 Granada, Spain
3
Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, Campus de Ceuta, University of Granada, 51001 Ceuta, Spain
4
Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, Campus de Melilla, University of Granada, 52005 Melilla, Spain
5
Department of Stomatology, School of Dentistry, University of Granada, 18071 Granada, Spain
6
Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, 18016 Granada, Spain
7
Institute of Neuroscience, University of Granada, 18071 Granada, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(22), 12215; https://doi.org/10.3390/ijms222212215
Submission received: 20 October 2021 / Revised: 6 November 2021 / Accepted: 10 November 2021 / Published: 11 November 2021
(This article belongs to the Special Issue Human Saliva as a Source of Biomarkers for Oral Diseases)
Browse Figure
Versions Notes

Abstract

:
Oral squamous cell carcinoma (OSCC) is the most prevalent oral malignant tumor worldwide. An early diagnosis can have a major positive impact on its prognosis. Human saliva contains cytokines, DNA and RNA molecules, circulating cells, and derivatives of tissues and extracellular vesicles, among other factors that can serve as biomarkers. Hence, the analysis of saliva may provide useful information for the early diagnosis of OSCC for its prognosis. The objective of this review was to determine the potential usefulness of salivary biomarkers (cytokines and microRNA) to diagnose OSCC and improve its prognosis. A combination of salivary miRNA and proteomic data could allow a definitive and early diagnosis to be obtained. However, there remains a need to optimize and standardize the protocols used to quantify miRNAs.

Graphical Abstract

1. Introduction

Oral squamous cell carcinoma (OSCC) is the most prevalent oral malignant tumor worldwide, with a five-year survival rate of only 50%. An early diagnosis by primary care physicians or odontologists can have a major positive impact on its prognosis. However, the absence of symptoms and the lack of awareness by patients of the risk factors (tobacco, betel quid and alcohol) mean that the diagnosis is often made at a late stage, worsening the prognosis and increasing the mortality rate [1,2,3].
The diagnostic method of choice is to take a biopsy for pathological study, but this is sometimes not ordered because of its invasive nature, a lack of appropriate professional training, or an inability to meet the economic cost. Brush biopsy or toluidine blue staining can provide an early diagnosis but are known to miss lesions in localizations of difficult access, limiting their reliability. Detection of OSCC by conventional cancer screening strategies is also hampered by the heterogeneity between and within tumors and by their dynamic behavior, with changes in their molecular profile over time and in response to treatment. More effective techniques are therefore needed in order to deliver an early and reliable diagnosis [4]. Molecular techniques have attracted increasing attention, with reports that they can offer an early and accurate diagnosis, increased therapeutic success, and a reduced recurrence rate [5].
Human saliva contains cytokines, DNA and RNA molecules, circulating cells, and derivatives of tissues and extracellular vesicles (EVs), among other factors that can serve as biomarkers. Hence, the analysis of saliva may provide useful information for the early diagnosis of OSCC for its prognosis [1]. The objective of this review was to determine the potential usefulness of salivary biomarkers (cytokines and microRNA) to diagnose OSCC and improve its prognosis.

2. Salivary MicroRNA (miRNA) in OSCC Diagnosis and Prognosis

MiRNAs are small single-chain RNA molecules (19–21 nucleotides) transcribed by cell polymerase RNA and subjected to a double sequential cut in the nucleus (primary miRNA) and cytoplasm (precursor miRNA) (Table 1). Therefore, depending on their level of complementarity with the target, they can inhibit messenger RNA (mRNA) or its translation [1,6,7].
MiRNAs can be released in body fluids as cell-free miRNAs associated with RNA binding proteins or selectively packed in extracellular vesicles [27]. MiRNAs are involved in regulation of various biological processes, such as cell differentiation, proliferation, apoptosis and in embryonic and tissue development. At the level of bone metabolism, various miRNAs are emerging that are involved in their regulation [28]. Their expression is not modified in body tissues or fluids and is frequently tumor-specific. They are also the main regulators of gene expression and are therefore vitally important to detect incipient malignant transformation. Accordingly, the analysis of miRNA profiles in patients with cancer represents a new paradigm in the development of biomarkers for the clinical diagnosis of this disease.
Furthermore, the expression of certain miRNAs in the tumor microenvironment has been associated with the dysregulation of oncosuppressors or oncogenes, contributing to the development or inhibition of tumors. MiRNAs can promote or inhibit the expression of target genes by directly binding with their target mRNA. They can also affect mRNA stability [29], and aberrant miRNA regulation can make a major contribution to the development of cancer [30]. In this way, miRNAs with oncogenic function are upregulated and responsible for silencing tumor-suppressor genes that can modulate the onset, development, and metastasis of cancer cells. Conversely, miRNAs with tumor-suppressor function are downregulated, reducing the modulation of oncogenes and maintaining malignity [8].

2.1. Exosomal miRNAs with Diagnostic Capacity

One advantage of salivary exosomal miRNA over other OSCC biomarkers is that it can be detected in small amounts of saliva and by analysis of the whole saliva sample or the supernatant. The following salivary exosomal miRNAs have been correlated with disease stage, histopathological type and/or grade: miRNA-24-3P, 412-3p, 512-3p, 302b-3p, 517b-3p, 134, 486-5p, 4484, 10b-5p, 200a, and 365 [8,9,10,11,31,32]. Notably, the expression of miRNA-34 was greater in high-grade OSCCs, and the expression of miRNA-486-5p assisted the detection of stage I OSCC, demonstrating the potential usefulness of salivary exosomal miRNAs for the early diagnosis of cancer [10]. In the same way, it has been found that miRNAs-4484 and 10b-5p are biomarkers of the malignant transformation of oral lichen planus and oral dysplasia in OSCC [8,10,11], and a lower expression of miRNA-200a has been associated with a higher risk of malignant transformation and oral cancer. Finally, miR-365 has been found to regulate transcription, promoting oncogenesis and metastasis in some cancers but suppressing these processes in others [12].

2.2. MiRNAs with Tumor-Suppressor Role

MiRNAs with a tumor-suppressor role include: miRNA-27b, which inhibits cell proliferation, migration, and invasion in OSCC [14]; miRNA-200 [33], which inhibits cell growth at increased salivary concentrations [13]; miRNA-375, found to act as tumor-suppressor in multiple cancers, including OSCC [15]; and miRNA-26a, which inhibits cell migration and metastasis and lowers the expression of enhancer of zeste homolog 2 (EZH2), reducing cell growth [17]. Many tumor-suppressor miRNAs act by inhibiting the expression of genes that promote cell proliferation. These include miRNA-7 [16], which inhibits the expression of epidermal growth factor receptor (EGFR), and miRNA-107, which inhibits Akt, Stat3, and Rho GTPases genes through protein kinase Cε (PKCε) [18]. Other tumor-suppressor miRNAs inhibit cell migration, invasion, and metastasis by interfering with signaling cascades, including: miR-218 [19], which inhibits the focal adhesion pathway, impeding cell migration; some members of the miRNA let-7 family [20]; and miRNA-125 [34].

2.3. MiRNAs with Tumor-Activator Role

All of the following miRNAs are detected at higher concentrations in the saliva of patients with OSCC versus healthy individuals, offering a reliable method to detect OSCC and potentially malignant oral lesions [21,22,23,24].
MiRNA-21 acts as an oncogene, promoting OSCC development and progression by inhibiting apoptosis [22]. It is a marker of malignant transformation, indicating a worse prognosis and reduced survival [1]. Aberrant expression of MiR-145 has also been found to indicate malignant transformation. MiRNA-93 has been associated with OSCC, showing elevated expression at 12 months post-radiotherapy [23]. This miRNA can be considered a valuable marker to predict the prognosis and risk of metastasis, given the significant relationship found between its high expression and T grade, lymph node metastases, and clinical stage [25]. For its part, miRNA-184 is the only miRNA to date that can differentiate between OSCC and premalignant dysplastic diseases [22]. MiRNA-31 has been reported to increase the proliferation, migration, and growth of OSCC cells in vitro and in mice models, increasing their oncogenic potential [26]. It does not differentiate among tumor stages but is a good indicator of the presence of lymphatic metastasis. MiR-412-3p is positively regulated and induces cancer progression via the transforming growth factor (TGF) pathway [25]. Finally, miRNA-34a is downregulated and differentially expressed in patients with leukoplakia versus healthy individuals and has been significantly associated with the locoregional aggressiveness of tumors and their histopathological grade [22].

2.4. Circular RNA in OSCC Diagnosis

It has recently been demonstrated that circular RNAs (circRNAs) can serve as potential molecular markers for the diagnosis of diseases, but few data have been published on their diagnostic potential for OSCC. Zhao et al. [35] observed that circRNAs hsa_circ_0001874, hsa_circ_0001971, and hsa_circ_0008068 were upregulated and hsa_circ_0000140, hsa_circ_0002632, and hsa_circ_0008792 were downregulated in patients with OSCC versus healthy individuals. Salivary hsa_circ_0001874 was correlated with TNM stage (p = 0.006) and tumor grade (p = 0.023) and hsa_circ_0001971 with TNM stage (p = 0.019), and salivary expressions of hsa_circ_0001874 and hsa_circ_0001971 were found to be lower in post-operative versus pre-operative samples (p < 0.001).

3. Salivary Cytokines in OSCC Diagnosis and Prognosis

Inflammatory processes are crucial in protecting against aggressions from external infectious agents, traumatic-type tissue injuries and tumor processes. During the process by which the body recognizes these different aggressions, the production of a wide variety of inflammatory and anti-inflammatory mediators is triggered, including cytokines [36].
Cytokines are proteins secreted by certain cell groups (mainly macrophages and helper T cells), with a very important role in immunomodulation processes. Dysregulation in the levels of certain cytokines is related to the appearance of various types of cancer, considering an important role as biomarkers for the diagnosis and monitoring of certain tumor processes [37] (Table 2).

3.1. IL-6

Interleukin-6 (IL-6) is an important proinflammatory cytokine produced by epithelial cells, mast cells, and hematopoietic line cells, among others. It plays a role in multiple organs and systems and has a major influence at immune level, being essential for host protection during the initial stages of infection; in addition, its concentration is elevated in inflammatory diseases [66,67,68,69,70].
Elevated IL-6 concentrations have been reported in the saliva of patients with OSCC [41,42,51,53,54], being related to the inflammatory process produced by the disease [71]. They have been detected at initial stages of OSCC [38,49] and in premalignant lesions related to its onset [47]. IL-6, alongside tumor necrosis factor alpha (TNF-α), was found to discriminate between OSCC and oral leukoplakia [38]. This cytokine, among other proinflammatory proteins, has been reported to promote tumor growth and invasion, epithelial-mesenchymal transition, and angiogenesis in patients with OSCC, increasing the immune resistance of the tumor [36,38,72]. Elevated IL-6 concentrations have been associated with greater aggressiveness and severity of the disease, reducing survival and increasing the recurrence rate [48,73,74]. Concentrations of IL-6 and TNF-α were both found to increase exponentially with the progression of OSCC [38], confirming the involvement of certain proinflammatory cytokines in this disease, promoting the survival and proliferation of malignant cells [51].

3.2. IL-8

Interleukin-8 (IL-8) is a chemotactic factor that plays a key role in inflammatory and angiogenesis processes [75] and has important immune functions [76]. High IL-8 expression has been detected in carcinogenic cells and tissues and in the peripheral blood of patients with cancer [75,77].
Numerous authors have described elevated salivary IL-8 concentrations in patients diagnosed with OSCC [38,43,53]. In common with IL-6, it is responsible for the growth and proliferation of tumor cells and for enhancing their immune escape mechanisms [78,79]. Sahibzada et al. associated IL-8 with the aggressiveness of OSCC and supported the diagnostic validity of serum and saliva concentrations of this interleukin, even for an early detection of the disease [80]. Elevated IL-8 concentrations have been described in patients with premalignant lesions such as lichen planus, oral leukoplakia, and oral submucosal fibrosis [47], and elevated concentrations of IL-6 and IL-8 in saliva and serum have been associated with reduced survival and an increased recurrence rate in OSCC [48].

3.3. TNF-α

TNF-α is a transmembrane protein with a central role in triggering inflammatory reactions of the innate immune system. Its production is induced by bacterial pathogens and other microorganisms, triggering a highly complex biological cascade that involves the production of multiple anti-inflammatory biomolecules [33,81]. Elevated concentrations have been found in cancer patients at the tumor site and in the blood as a tumor survival mechanism [82,83]. As in the case of IL-6 and IL-8, this proinflammatory molecule is implicated in the growth, proliferation, and immune escape of tumor cells [78].
Its presence in saliva is elevated in patients with OSCC and is even detected at initial stages of the disease, increasing with disease progression and permitting differentiation between OSCC and oral leukoplakia [38]. Elevated concentrations of this and other biomolecules have also been found in premalignant lesions associated with progression to OSCC. Krishnan et al. [50] reported that TNF-α was highly overexpressed in patients with stage IV OSCC in comparison to patients with stages I, II, or IIIF, supporting its relationship with advanced stages of the disease.

3.4. MMP-9

Matrix metallopeptidase 9 (MMP-9), a protein of the endopeptidase family, degrades proteins of the extracellular matrix and participates in its remodeling in different physiological and pathological processes. This degradation of the extracellular matrix plays an important role in tumor invasion and metastasis, and MMP-9 overexpression has been used by some authors to distinguish among different types of cancer [84,85].
The presence of MMP-9 in saliva has been associated with OSCC, and its study has been proposed as a useful non-invasive approach to obtain an early diagnosis [44,45]. Shin et al. [39] reported that lower MMP-9 concentrations in patients with OSCC after than before surgery also indicate the possible prognostic value of this biomarker.

3.5. IL-1-β

Interleukin-1-β (IL-1-β), which acts as mediator of the immune response, is well known for its pyrogenic properties and its capacity to activate lymphocytes, stimulating their proliferation and differentiation. Its production is mediated by an inflammasome complex, and it plays a major role in the activation of various intracellular signaling cascades. IL-1-β secretion promotes numerous metabolic, physiological, and inflammatory effects, and an excess of this cytokine can produce tissue damage associated with multiple inflammatory and autoimmune diseases [86,87,88,89].
IL-1-β concentrations in both stimulated and non-stimulated saliva samples are markedly higher in patients with OSCC than in healthy patients [90]. Li et al. [40] found an elevated expression of this cytokine not only in saliva but also in neoplastic tissue from patients, especially in the initial stages of OSCC, indicating the potential diagnostic value of this biomarker. IL-1-β has been found to have diagnostic value across populations with different ethnicities. However, it is not pathognomonic, because concentrations can be increased in patients with other inflammatory diseases of the oral cavity, including periodontitis; hence, concentrations of other biomarkers must also be considered to establish a diagnosis [56]. Kamatani et al. [57] reported a decrease in salivary IL-1β after the surgical resection of OSCC, supporting the diagnostic usefulness of this cytokine to detect disease recurrence.

3.6. IL-1-Ra

IL-1 receptor antagonist (IL-1-Ra) binds to the membrane cell receptor of IL-1 without producing an intracellular effect, impeding the binding of IL-1 and acting as its negative regulator. IL-1-Ra is mainly produced by activated monocytes, macrophages, neutrophils, and fibroblasts after their stimulation by lipopolysaccharide, triggering a cascade of proinflammatory cytokines (e.g., IL-1 or TNF) in a first phase and a cascade of inflammation mediators (e.g., IL-10 or IL-1-Ra) in a second. IL-1-Ra has a much lower affinity for the receptor in comparison to IL-1 and needs higher concentrations to fulfill its function [58].
Niklander et al. [58] found that IL-1-Ra is constitutively expressed in normal oral epithelium but shows a reduced expression in neoplastic tissue. Its expression decreases in both primary cultures and dysplastic cells with senescence, consistent with the higher frequency of OSCC among people over the age of 50 years [91]. IL-1-Ra overexpression has been detected in dysplastic and neoplastic cells and may, alongside the overexpression of IL-1 β, favor cancer growth by regulating CD184 expression. Shiiba et al. [59] reported that IL-1-Ra had a sensitivity of 70% and specificity of 85% to discriminate between OSCC, in which it is upregulated, and other potentially malignant oral cavity diseases such as lichen planus. However, inadequate data are available on variations in its concentration over the course of OSCC, reducing its value as a prognostic marker [60,92].

3.7. IL-10

IL-10 is an anti-inflammatory cytokine that inhibits the synthesis of proinflammatory cytokines (e.g., IFN-γ, IL-2, IL-3, or TNF-α) by T lymphocytes and macrophages and interferes with the activity of antigen-presenting cells [93].
Elevated concentrations of this cytokine have been found in patients with OSCC [60,94,95], and very high concentrations have been associated with aggressive phenotypes of this disease, implying a worse prognosis. Suppression by IL-10 of antitumor immunity mechanisms (preventing antigen presentation from transformed cancer cells to cytotoxic T cells) favors propagation of the cancer and reduces patient survival [94,95]; IL-10 can therefore serve as a prognostic biomarker, especially at early stages of the disease. IL-10 production is very high at advanced stages due to its abundant expression by metastatic tissues, maintaining an environment that favors the proliferation and expansion of neoplastic cells that in turn segregate IL-10, in a vicious cycle [61].

3.8. 8-OHdG (8-Oxo-dG)

8-Oxo-2′-deoxyguanosine (8-OHdG) is a derivative of deoxyguanosine and one of the main products of DNA oxidization. It is a direct biomarker of cellular oxidative stress, which activates the expression of inflammatory genes through an enzymatic cascade, thereby contributing to carcinogenesis. Hence, 8-OHdG8 acts via a dual mechanism: gene expression and gene damage mutations by oxidization. Although it may be less well known in comparison to interleukins, 8-OHdG has demonstrated very high diagnostic value, with numerous studies reporting a strong correlation between its concentration and the presence of cancer [64,96,97,98,99].
Salivary concentrations of this biomarker were found to significantly differ among healthy individuals, patients with premalignant diseases of the oral cavity, and patients with OSCC, supporting its diagnostic and prognostic value. In the same line, Kumar et al. [64] observed that 8-OHdG, alongside reactive oxygen species and nitrogen, is more abundant in saliva from patients with head and neck squamous cell carcinoma in comparison to healthy individuals and that glutathione concentrations and total antioxidant capacity are significantly lower. However, other salivary biomarkers must be taken into consideration to establish a diagnosis, because elevated concentrations have also been detected in patients with periodontitis, who show much higher concentrations of 8-OHdG in comparison to other markers of oxidative stress, although they can be normalized by the administration of anti-inflammatories [100].

4. Conclusions

Accumulated evidence indicates that the measurement of miRNAs and certain oral cytokines in saliva is a highly promising technique for the diagnosis and prognosis of OSCC. A combination of salivary miRNA and proteomic data could allow a definitive and early diagnosis to be obtained. The analysis of these salivary biomarkers together with the study of other histopathological markers such as the presence of eosinophils and the immune phenotype could be a key factor in developing new strategies in OSCC treatment [101,102]. The main limitation of this review is that the included studies show high heterogeneity with respect to the methods and protocols used for miRNA and cytokines analysis. In addition, the cohort of patients in some of these studies is small. Therefore, there remains a need to optimize and standardize these protocols and design new studies with larger patient cohorts.

Author Contributions

F.J.M.-M. formulated the research question. C.R.-B. and C.R. conceived and designed the study. All authors contributed to the discussion and study design. F.J.M.-M., V.J.C.-R., E.G.-R. and M.V.O.-G. conducted the bibliographic search and data collection. All authors interpreted the results and drafted the manuscript. F.J.M.-M., V.J.C.-R., E.G.-R. and M.V.O.-G. created the table. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

This study was supported by research group BIO277 (Junta de Andalucía), Department of Nursing (University of Granada) and Department of Stomatology (University of Granada).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

OSCCOral squamous cell carcinoma
EVsExtracellular vesicles
EZH2Enhancer of zeste homolog 2
EGFREpidermal growth factor receptor
PKCεProtein kinase Cε
TGFTransforming growth factor
circRNAsCircular RNAs
IL-6Interleukin-6
TNF-αTumor necrosis factor alpha
IL-8Interleukin-8
MMP-9Matrix metallopeptidase 9
IL-1-βInterleukin-1-β
IL-1-RaIL-1 receptor antagonist
IL-10Interleukin-10
8-OHdG (8-oxo-dG)8-Oxo-2′-deoxyguanosine

References

  1. Cristaldi, M.; Mauceri, R.; Di Fede, O.; Giuliana, G.; Campisi, G.; Panzarella, V. Salivary Biomarkers for Oral Squamous Cell Carcinoma Diagnosis and Follow-Up: Current Status and Perspectives. Front. Physiol. 2019, 10, 1476. [Google Scholar] [CrossRef]
  2. Guha, N.; Warnakulasuriya, S.; Vlaanderen, J.; Straif, K. Betel quid chewing and the risk of oral and oropharyngeal cancers: A meta-analysis with implications for cancer control. Int. J. Cancer 2014, 135, 1433–1443. [Google Scholar] [CrossRef]
  3. Jeng, J.H.; Chang, M.C.; Hahn, L.J. Role of areca nut in betel quid-associated chemical carcinogenesis: Current awareness and future perspectives. Oral Oncol. 2001, 37, 477–492. [Google Scholar] [CrossRef]
  4. Bellairs, J.A.; Hasina, R.; Agrawal, N. Tumor DNA: An emerging biomarker in head and neck cancer. Cancer Metastasis Rev. 2017, 36, 515–523. [Google Scholar] [CrossRef]
  5. Woolgar, J.A. Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol. 2006, 42, 229–239. [Google Scholar] [CrossRef]
  6. Bartel, D.P. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell 2004, 116, 281–297. [Google Scholar] [CrossRef] [Green Version]
  7. Perron, M.P.; Provost, P. Protein interactions and complexes in human microRNA biogenesis and function. Front. Biosci. 2008, 13, 2537–2547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Faur, C.I.; Rotaru, H.; Osan, C.; Jurj, A.; Roman, R.C.; Moldovan, M.; Chirila, M.; Hedesiu, M. Salivary exosomal microRNAs as biomarkers for head and neck cancer detection-a literature review. Maxillofac. Plast. Reconstr. Surg. 2021, 43, 19. [Google Scholar] [CrossRef] [PubMed]
  9. He, L.; Ping, F.; Fan, Z.; Zhang, C.; Deng, M.; Cheng, B.; Xia, J. Salivary exosomal miR-24-3p serves as a potential detective biomarker for oral squamous cell carcinoma screening. Biomed. Pharmacother. 2020, 121, 109553. [Google Scholar] [CrossRef] [PubMed]
  10. Langevin, S.; Kuhnell, D.; Parry, T.; Biesiada, J.; Huang, S.; Wise-Draper, T.; Casper, K.; Zhang, X.; Medvedovic, M.; Kasper, S. Comprehensive microRNA-sequencing of exosomes derived from head and neck carcinoma cells in vitro reveals common secretion profiles and potential utility as salivary biomarkers. Oncotarget 2017, 8, 82459–82474. [Google Scholar] [CrossRef] [Green Version]
  11. Byun, J.-S.; Hong, S.-H.; Choi, J.-K.; Jung, J.-K.; Lee, H.-J. Diagnostic profiling of salivary exosomal microRNAs in oral lichen planus patients. Oral Dis. 2015, 21, 987–993. [Google Scholar] [CrossRef]
  12. Coon, J.; Kingsley, K.; Howard, K.M. miR-365 (microRNA): Potential Biomarker in Oral Squamous Cell Carcinoma Exosomes and Extracellular Vesicles. Int. J. Mol. Sci. 2020, 21, 5317. [Google Scholar] [CrossRef] [PubMed]
  13. Al Rawi, N.; Elmabrouk, N.; Abu Kou, R.; Mkadmi, S.; Rizvi, Z.; Hamdoon, Z. The role of differentially expressed salivary microRNA in oral squamous cell carcinoma. A systematic review. Arch. Oral Biol. 2021, 125, 105108. [Google Scholar] [CrossRef] [PubMed]
  14. Momen-Heravi, F.; Bala, S. Emerging role of non-coding RNA in oral cancer. Cell. Signal. 2018, 42, 134–143. [Google Scholar] [CrossRef] [PubMed]
  15. Harris, T.; Jimenez, L.; Kawachi, N.; Fan, J.-B.; Chen, J.; Belbin, T.; Ramnauth, A.; Loudig, O.; Keller, C.E.; Smith, R.; et al. Low-level expression of miR-375 correlates with poor outcome and metastasis while altering the invasive properties of head and neck squamous cell carcinomas. Am. J. Pathol. 2012, 180, 917–928. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Kalinowski, F.C.; Giles, K.M.; Candy, P.A.; Ali, A.; Ganda, C.; Epis, M.R.; Webster, R.J.; Leedman, P.J. Regulation of epidermal growth factor receptor signaling and erlotinib sensitivity in head and neck cancer cells by miR-7. PLoS ONE 2012, 7, e47067. [Google Scholar] [CrossRef]
  17. Lu, Z.-M.; Lin, Y.-F.; Jiang, L.; Chen, L.-S.; Luo, X.-N.; Song, X.-H.; Chen, S.-H.; Zhang, S.-Y. Micro-ribonucleic acid expression profiling and bioinformatic target gene analyses in laryngeal carcinoma. OncoTargets Ther. 2014, 7, 525–533. [Google Scholar] [CrossRef] [Green Version]
  18. Datta, J.; Smith, A.; Lang, J.C.; Islam, M.; Dutt, D.; Teknos, T.N.; Pan, Q. microRNA-107 functions as a candidate tumor-suppressor gene in head and neck squamous cell carcinoma by downregulation of protein kinase Cɛ. Oncogene 2012, 31, 4045–4053. [Google Scholar] [CrossRef] [Green Version]
  19. Kinoshita, T.; Nohata, N.; Hanazawa, T.; Kikkawa, N.; Yamamoto, N.; Yoshino, H.; Itesako, T.; Enokida, H.; Nakagawa, M.; Okamoto, Y.; et al. Tumour-suppressive microRNA-29s inhibit cancer cell migration and invasion by targeting laminin-integrin signalling in head and neck squamous cell carcinoma. Br. J. Cancer 2013, 109, 2636–2645. [Google Scholar] [CrossRef] [Green Version]
  20. Alajez, N.M.; Shi, W.; Wong, D.; Lenarduzzi, M.; Waldron, J.; Weinreb, I.; Liu, F.-F. Lin28b Promotes Head and Neck Cancer Progression via Modulation of the Insulin-Like Growth Factor Survival Pathway. Oncotarget 2012, 3, 1641–1652. [Google Scholar] [CrossRef] [Green Version]
  21. Wiklund, E.D.; Gao, S.; Hulf, T.; Sibbritt, T.; Nair, S.; Costea, D.E.; Villadsen, S.B.; Bakholdt, V.; Bramsen, J.B.; Sørensen, J.A.; et al. MicroRNA alterations and associated aberrant DNA methylation patterns across multiple sample types in oral squamous cell carcinoma. PLoS ONE 2011, 6, e27840. [Google Scholar] [CrossRef]
  22. Zahran, F.; Ghalwash, D.; Shaker, O.; Al-Johani, K.; Scully, C. Salivary microRNAs in oral cancer. Oral Dis. 2015, 21, 739–747. [Google Scholar] [CrossRef]
  23. Greither, T.; Vorwerk, F.; Kappler, M.; Bache, M.; Taubert, H.; Kuhnt, T.; Hey, J.; Eckert, A.W. Salivary miR-93 and miR-200a as post-radiotherapy biomarkers in head and neck squamous cell carcinoma. Oncol. Rep. 2017, 38, 1268–1275. [Google Scholar] [CrossRef] [Green Version]
  24. Maheswari, T.N.U.; Venugopal, A.; Sureshbabu, N.M.; Ramani, P. Salivary micro RNA as a potential biomarker in oral potentially malignant disorders: A systematic review. Tzu-Chi Med. J. 2018, 30, 55–60. [Google Scholar] [CrossRef] [PubMed]
  25. Liu, D.; Xin, Z.; Guo, S.; Li, S.; Cheng, J.; Jiang, H. Blood and Salivary MicroRNAs for Diagnosis of Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. J. Oral Maxillofac. Surg. 2021, 79, 1082.e1–1082.e13. [Google Scholar] [CrossRef] [PubMed]
  26. Hung, P.-S.; Liu, C.-J.; Chou, C.-S.; Kao, S.-Y.; Yang, C.-C.; Chang, K.-W.; Chiu, T.-H.; Lin, S.-C. miR-146a Enhances the Oncogenicity of Oral Carcinoma by Concomitant Targeting of the IRAK1, TRAF6 and NUMB Genes. PLoS ONE 2013, 8, e79926. [Google Scholar] [CrossRef]
  27. Larrea, E.; Sole, C.; Manterola, L.; Goicoechea, I.; Armesto, M.; Arestin, M.; Caffarel, M.M.; Araujo, A.M.; Araiz, M.; Fernandez-Mercado, M.; et al. New Concepts in Cancer Biomarkers: Circulating miRNAs in Liquid Biopsies. Int. J. Mol. Sci. 2016, 17, 627. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Giner, M.; Montoya, M.J.; Vázquez, M.A.; Miranda, C.; Miranda, M.J.; Pérez-Cano, R. ¿Qué son los microARNs?: Posibles biomarcadores y dianas terapéuticas en la enfermedad osteoporótica. Rev. Osteoporos. Metab. Min. 2016, 8, 40–44. [Google Scholar] [CrossRef] [Green Version]
  29. Wu, B.; Xiong, X.; Jia, J.; Zhang, W. MicroRNAs: New actors in the oral cancer scene. Oral Oncol. 2011, 47, 314–319. [Google Scholar] [CrossRef]
  30. Sannigrahi, M.K.; Sharma, R.; Singh, V.; Panda, N.K.; Rattan, V.; Khullar, M. Role of Host miRNA Hsa-miR-139-3p in HPV-16-Induced Carcinomas. Clin. Cancer Res. 2017, 23, 3884–3895. [Google Scholar] [CrossRef] [Green Version]
  31. Gai, C.; Camussi, F.; Broccoletti, R.; Gambino, A.; Cabras, M.; Molinaro, L.; Carossa, S.; Camussi, G.; Arduino, P.G. Salivary extracellular vesicle-associated miRNAs as potential biomarkers in oral squamous cell carcinoma. BMC Cancer 2018, 18, 439. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Farag, A.F.; Sabry, D.; Hassabou, N.F.; Alaa EL-Din, Y. MicroRNA-134/MicroRNA-200a Derived Salivary Exosomes are Novel Diagnostic Biomarkers of Oral Squamous Cell Carcinoma. Egypt. Dent. J. 2021, 67, 367–377. [Google Scholar] [CrossRef]
  33. Akira, S.; Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 2004, 4, 499–511. [Google Scholar] [CrossRef] [PubMed]
  34. Dlamini, Z.; Alaouna, M.; Mbatha, S.; Bhayat, A.; Mabongo, M.; Chatziioannou, A.; Hull, R. Genetic Drivers of Head and Neck Squamous Cell Carcinoma: Aberrant Splicing Events, Mutational Burden, HPV Infection and Future Targets. Genes 2021, 12, 422. [Google Scholar] [CrossRef] [PubMed]
  35. Zhao, S.-Y.; Wang, J.; Ouyang, S.-B.; Huang, Z.-K.; Liao, L. Salivary Circular RNAs Hsa_Circ_0001874 and Hsa_Circ_0001971 as Novel Biomarkers for the Diagnosis of Oral Squamous Cell Carcinoma. Cell. Physiol. Biochem. 2018, 47, 2511–2521. [Google Scholar] [CrossRef]
  36. Landskron, G.; De la Fuente, M.; Thuwajit, P.; Thuwajit, C.; Hermoso, M.A. Chronic inflammation and cytokines in the tumor microenvironment. J. Immunol. Res. 2014, 2014, 149185. [Google Scholar] [CrossRef] [Green Version]
  37. Loo, S.W.; Pui, T.-S. Cytokine and Cancer Biomarkers Detection: The Dawn of Electrochemical Paper-Based Biosensor. Sensors 2020, 20, 1854. [Google Scholar] [CrossRef] [Green Version]
  38. Dikova, V.; Jantus-Lewintre, E.; Bagan, J. Potential Non-Invasive Biomarkers for Early Diagnosis of Oral Squamous Cell Carcinoma. J. Clin. Med. 2021, 10, 1658. [Google Scholar] [CrossRef]
  39. Shin, Y.-J.; Vu, H.; Lee, J.-H.; Kim, H.-D. Diagnostic and prognostic ability of salivary MMP-9 for oral squamous cell carcinoma: A pre-/post-surgery case and matched control study. PLoS ONE 2021, 16, e0248167. [Google Scholar] [CrossRef]
  40. Lee, L.T.; Wong, Y.K.; Hsiao, H.Y.; Wang, Y.W.; Chan, M.Y.; Chang, K.W. Evaluation of saliva and plasma cytokine biomarkers in patients with oral squamous cell carcinoma. Int. J. Oral Maxillofac. Surg. 2018, 47, 699–707. [Google Scholar] [CrossRef]
  41. Vesty, A.; Gear, K.; Biswas, K.; Radcliff, F.J.; Taylor, M.W.; Douglas, R.G. Microbial and inflammatory-based salivary biomarkers of head and neck squamous cell carcinoma. Clin. Exp. Dent. Res. 2018, 4, 255–262. [Google Scholar] [CrossRef] [Green Version]
  42. Khyani, I.A.M.; Qureshi, M.A.; Mirza, T.; Farooq, M.U. Detection of interleukins-6 and 8 in saliva as potential biomarkers of oral pre-malignant lesion and oral carcinoma: A breakthrough in salivary diagnostics in Pakistan. Pak. J. Pharm. Sci. 2017, 30, 817–823. [Google Scholar]
  43. Csősz, É.; Lábiscsák, P.; Kalló, G.; Márkus, B.; Emri, M.; Szabó, A.; Tar, I.; Tőzsér, J.; Kiss, C.; Márton, I. Proteomics investigation of OSCC-specific salivary biomarkers in a Hungarian population highlights the importance of identification of population-tailored biomarkers. PLoS ONE 2017, 12, e0177282. [Google Scholar] [CrossRef] [Green Version]
  44. Ghallab, N.A.; Shaker, O.G. Serum and salivary levels of chemerin and MMP-9 in oral squamous cell carcinoma and oral premalignant lesions. Clin. Oral Investig. 2017, 21, 937–947. [Google Scholar] [CrossRef]
  45. Peisker, A.; Raschke, G.-F.; Fahmy, M.-D.; Guentsch, A.; Roshanghias, K.; Hennings, J.; Schultze-Mosgau, S. Salivary MMP-9 in the detection of oral squamous cell carcinoma. Med. Oral Patol. Oral Cir. Bucal 2017, 22, e270–e275. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Gleber-Netto, F.O.; Yakob, M.; Li, F.; Feng, Z.; Dai, J.; Kao, H.-K.; Chang, Y.-L.; Chang, K.-P.; Wong, D.T.W. Salivary Biomarkers for Detection of Oral Squamous Cell Carcinoma in a Taiwanese Population. Clin. Cancer Res. 2016, 22, 3340–3347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Kaur, J.; Jacobs, R. Proinflammatory cytokine levels in oral lichen planus, oral leukoplakia, and oral submucous fibrosis. J. Korean Assoc. Oral Maxillofac. Surg. 2015, 41, 171–175. [Google Scholar] [CrossRef] [Green Version]
  48. Arduino, P.G.; Menegatti, E.; Cappello, N.; Martina, E.; Gardino, N.; Tanteri, C.; Cavallo, F.; Scully, C.; Broccoletti, R. Possible role for interleukins as biomarkers for mortality and recurrence in oral cancer. Int. J. Biol. Markers 2015, 30, e262–e266. [Google Scholar] [CrossRef] [PubMed]
  49. Lisa Cheng, Y.-S.; Jordan, L.; Gorugantula, L.M.; Schneiderman, E.; Chen, H.-S.; Rees, T. Salivary interleukin-6 and -8 in patients with oral cancer and patients with chronic oral inflammatory diseases. J. Periodontol. 2014, 85, 956–965. [Google Scholar] [CrossRef]
  50. Krishnan, R.; Thayalan, D.K.; Padmanaban, R.; Ramadas, R.; Annasamy, R.K.; Anandan, N. Association of serum and salivary tumor necrosis factor-α with histological grading in oral cancer and its role in differentiating premalignant and malignant oral disease. Asian Pac. J. Cancer Prev. 2014, 15, 7141–7148. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Brailo, V.; Vucicevic-Boras, V.; Lukac, J.; Biocina-Lukenda, D.; Zilic-Alajbeg, I.; Milenovic, A.; Balija, M. Salivary and serum interleukin 1 beta, interleukin 6 and tumor necrosis factor alpha in patients with leukoplakia and oral cancer. Med. Oral Patol. Oral Cir. Bucal 2012, 17, e10–e15. [Google Scholar] [CrossRef]
  52. Korostoff, A.; Reder, L.; Masood, R.; Sinha, U.K. The role of salivary cytokine biomarkers in tongue cancer invasion and mortality. Oral Oncol. 2011, 47, 282–287. [Google Scholar] [CrossRef] [PubMed]
  53. Katakura, A.; Kamiyama, I.; Takano, N.; Shibahara, T.; Muramatsu, T.; Ishihara, K.; Takagi, R.; Shouno, T. Comparison of salivary cytokine levels in oral cancer patients and healthy subjects. Bull. Tokyo Dent. Coll. 2007, 48, 199–203. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Rhodus, N.L.; Ho, V.; Miller, C.S.; Myers, S.; Ondrey, F. NF-kappaB dependent cytokine levels in saliva of patients with oral preneoplastic lesions and oral squamous cell carcinoma. Cancer Detect. Prev. 2005, 29, 42–45. [Google Scholar] [CrossRef] [PubMed]
  55. Li, Y.; John, M.A.R.S.; Zhou, X.; Kim, Y.; Sinha, U.; Jordan, R.C.K.; Eisele, D.; Abemayor, E.; Elashoff, D.; Park, N.-H.; et al. Salivary Transcriptome Diagnostics for Oral Cancer Detection. Clin. Cancer Res. 2004, 10, 8442–8450. [Google Scholar] [CrossRef] [Green Version]
  56. Brinkmann, O.; Kastratovic, D.A.; Dimitrijevic, M.V.; Konstantinovic, V.S.; Jelovac, D.B.; Antic, J.; Nesic, V.S.; Markovic, S.Z.; Martinovic, Z.R.; Akin, D.; et al. Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population. Oral Oncol. 2011, 47, 51–55. [Google Scholar] [CrossRef] [Green Version]
  57. Kamatani, T.; Shiogama, S.; Yoshihama, Y.; Kondo, S.; Shirota, T.; Shintani, S. Interleukin-1 beta in unstimulated whole saliva is a potential biomarker for oral squamous cell carcinoma. Cytokine 2013, 64, 497–502. [Google Scholar] [CrossRef]
  58. Niklander, S.E. Inflammatory Mediators in Oral Cancer: Pathogenic Mechanisms and Diagnostic Potential. Front. Oral Health 2021, 2, 2. [Google Scholar] [CrossRef]
  59. Shiiba, M.; Saito, K.; Yamagami, H.; Nakashima, D.; Higo, M.; Kasamatsu, A.; Sakamoto, Y.; Ogawara, K.; Uzawa, K.; Takiguchi, Y.; et al. Interleukin-1 receptor antagonist (IL1RN) is associated with suppression of early carcinogenic events in human oral malignancies. Int. J. Oncol. 2015, 46, 1978–1984. [Google Scholar] [CrossRef] [Green Version]
  60. Aziz, S.; Ahmed, S.S.; Ali, A.; Khan, F.A.; Zulfiqar, G.; Iqbal, J.; Khan, A.A.; Shoaib, M. Salivary Immunosuppressive Cytokines IL-10 and IL-13 Are Significantly Elevated in Oral Squamous Cell Carcinoma Patients. Cancer Investig. 2015, 33, 318–328. [Google Scholar] [CrossRef]
  61. Arantes, L.M.R.B.; De Carvalho, A.C.; Melendez, M.E.; Lopes Carvalho, A. Serum, plasma and saliva biomarkers for head and neck cancer. Expert Rev. Mol. Diagn. 2018, 18, 85–112. [Google Scholar] [CrossRef] [PubMed]
  62. Chen, C.-J.; Sung, W.-W.; Su, T.-C.; Chen, M.-K.; Wu, P.-R.; Yeh, K.-T.; Ko, J.-L.; Lee, H. High expression of interleukin 10 might predict poor prognosis in early stage oral squamous cell carcinoma patients. Clin. Chim. Acta 2013, 415, 25–30. [Google Scholar] [CrossRef]
  63. Sun, Y.; Liu, N.; Guan, X.; Wu, H.; Sun, Z.; Zeng, H. Immunosuppression Induced by Chronic Inflammation and the Progression to Oral Squamous Cell Carcinoma. Mediat. Inflamm. 2016, 2016, 5715719. [Google Scholar] [CrossRef] [PubMed]
  64. Kumar, A.; Pant, M.C.; Singh, H.S.; Khandelwal, S. Determinants of oxidative stress and DNA damage (8-OhdG) in squamous cell carcinoma of head and neck. Indian J. Cancer 2012, 49, 309. [Google Scholar] [CrossRef]
  65. Nandakumar, A.; Nataraj, P.; James, A.; Krishnan, R.; K M, M. Estimation of Salivary 8-Hydroxydeoxyguanosine (8-OHdG) as a Potential Biomarker in Assessing Progression towards Malignancy: A Case-Control Study. Asian Pac. J. Cancer Prev. 2020, 21, 2325–2329. [Google Scholar] [CrossRef]
  66. Anderson, P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nat. Rev. Immunol. 2010, 10, 24–35. [Google Scholar] [CrossRef] [PubMed]
  67. Hop, H.T.; Huy, T.X.N.; Reyes, A.W.B.; Arayan, L.T.; Vu, S.H.; Min, W.; Lee, H.J.; Kang, C.K.; Kim, D.H.; Tark, D.S.; et al. Interleukin 6 Promotes Brucella abortus Clearance by Controlling Bactericidal Activity of Macrophages and CD8+ T Cell Differentiation. Infect. Immun. 2019, 87, e00431-19. [Google Scholar] [CrossRef] [Green Version]
  68. Kang, S.; Tanaka, T.; Narazaki, M.; Kishimoto, T. Targeting Interleukin-6 Signaling in Clinic. Immunity 2019, 50, 1007–1023. [Google Scholar] [CrossRef]
  69. Mauer, J.; Denson, J.L.; Brüning, J.C. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 2015, 36, 92–101. [Google Scholar] [CrossRef]
  70. Tanaka, T.; Narazaki, M.; Kishimoto, T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 2014, 6, a016295. [Google Scholar] [CrossRef]
  71. Sasaki, M.; Kodama, Y.; Shimoyama, Y.; Ishikawa, T.; Kimura, S. Aciduricity and acid tolerance mechanisms of Streptococcus anginosus. J. Gen. Appl. Microbiol. 2018, 64, 174–179. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Roi, A.; Roi, C.I.; Negruțiu, M.L.; Riviș, M.; Sinescu, C.; Rusu, L.-C. The Challenges of OSCC Diagnosis: Salivary Cytokines as Potential Biomarkers. J. Clin. Med. 2020, 9, 2866. [Google Scholar] [CrossRef]
  73. Duffy, S.A.; Taylor, J.M.G.; Terrell, J.E.; Islam, M.; Li, Y.; Fowler, K.E.; Wolf, G.T.; Teknos, T.N. Interleukin-6 predicts recurrence and survival among head and neck cancer patients. Cancer 2008, 113, 750–757. [Google Scholar] [CrossRef]
  74. Ferrari, E.; Pezzi, M.E.; Cassi, D.; Pertinhez, T.A.; Spisni, A.; Meleti, M. Salivary Cytokines as Biomarkers for Oral Squamous Cell Carcinoma: A Systematic Review. Int. J. Mol. Sci. 2021, 22, 6795. [Google Scholar] [CrossRef] [PubMed]
  75. Kim, J.-H. Interleukin-8 in the Tumor Immune Niche: Lessons from Comparative Oncology. In Tumor Microenvironment: The Role of Interleukins—Part A; Birbrair, A., Ed.; Advances in Experimental Medicine and Biology; Springer International Publishing: Cham, Switzerland, 2020; pp. 25–33. ISBN 978-3-030-38315-2. [Google Scholar]
  76. Baggiolini, M.; Walz, A.; Kunkel, S.L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J. Clin. Investig. 1989, 84, 1045–1049. [Google Scholar] [CrossRef]
  77. Waugh, D.J.J.; Wilson, C. The interleukin-8 pathway in cancer. Clin. Cancer Res. 2008, 14, 6735–6741. [Google Scholar] [CrossRef] [Green Version]
  78. Ben-Baruch, A. Inflammation-associated immune suppression in cancer: The roles played by cytokines, chemokines and additional mediators. Semin. Cancer Biol. 2006, 16, 38–52. [Google Scholar] [CrossRef]
  79. Cavaillon, J.M. Pro- versus anti-inflammatory cytokines: Myth or reality. Cell. Mol. Biol. 2001, 47, 695–702. [Google Scholar]
  80. Sahibzada, H.A.; Khurshid, Z.; Sannam Khan, R.; Naseem, M.; Mahmood Siddique, K.; Mali, M.; Zafar, M.S. Salivary IL-8, IL-6 and TNF-α as Potential Diagnostic Biomarkers for Oral Cancer. Diagnostics 2017, 7, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  81. Balkwill, F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006, 25, 409–416. [Google Scholar] [CrossRef]
  82. Aderka, D.; Englemann, H.; Hornik, V.; Skornick, Y.; Levo, Y.; Wallach, D.; Kushtai, G. Increased serum levels of soluble receptors for tumor necrosis factor in cancer patients. Cancer Res. 1991, 51, 5602–5607. [Google Scholar]
  83. Selinsky, C.L.; Boroughs, K.L.; Halsey, W.A.; Howell, M.D. Multifaceted inhibition of anti-tumour immune mechanisms by soluble tumour necrosis factor receptor type I. Immunology 1998, 94, 88–93. [Google Scholar] [CrossRef]
  84. Huang, H. Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances. Sensors 2018, 18, 3249. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Nagase, H.; Visse, R.; Murphy, G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 2006, 69, 562–573. [Google Scholar] [CrossRef] [Green Version]
  86. Ren, K.; Torres, R. Role of interleukin-1β during pain and inflammation. Brain Res. Rev. 2009, 60, 57–64. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Abderrazak, A.; Syrovets, T.; Couchie, D.; El Hadri, K.; Friguet, B.; Simmet, T.; Rouis, M. NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases. Redox Biol. 2015, 4, 296–307. [Google Scholar] [CrossRef]
  88. Lin, C.-C.; Edelson, B.T. New Insights into the Role of IL-1β in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. J. Immunol. 2017, 198, 4553–4560. [Google Scholar] [CrossRef] [Green Version]
  89. Kanneganti, T.-D. Intracellular innate immune receptors: Life inside the cell. Immunol. Rev. 2020, 297, 5–12. [Google Scholar] [CrossRef]
  90. Radhika, T.; Jeddy, N.; Nithya, S.; Muthumeenakshi, R.M. Salivary biomarkers in oral squamous cell carcinoma—An insight. J. Oral Biol. Craniofac. Res. 2016, 6, S51–S54. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Acharya, S.; Tayaar, A.S. Analysis of clinical and histopathological profiles of oral squamous cell carcinoma in young Indian adults: A retrospective study. J. Dent. Sci. 2012, 7, 224–230. [Google Scholar] [CrossRef] [Green Version]
  92. Liu, K.Y.P.; Lu, X.J.D.; Zhu, Y.S.; Le, N.; Kim, H.; Poh, C.F. Plasma-Derived Inflammatory Proteins Predict Oral Squamous Cell Carcinoma. Front. Oncol. 2018, 8, 585. [Google Scholar] [CrossRef]
  93. Sabat, R.; Grütz, G.; Warszawska, K.; Kirsch, S.; Witte, E.; Wolk, K.; Geginat, J. Biology of interleukin-10. Cytokine Growth Factor Rev. 2010, 21, 331–344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Alhamarneh, O.; Agada, F.; Madden, L.; Stafford, N.; Greenman, J. Serum IL10 and circulating CD4(+) CD25(high) regulatory T cell numbers as predictors of clinical outcome and survival in patients with head and neck squamous cell carcinoma. Head Neck 2011, 33, 415–423. [Google Scholar] [CrossRef]
  95. Arantes, D.A.C.; Costa, N.L.; Mendonça, E.F.; Silva, T.A.; Batista, A.C. Overexpression of immunosuppressive cytokines is associated with poorer clinical stage of oral squamous cell carcinoma. Arch. Oral Biol. 2016, 61, 28–35. [Google Scholar] [CrossRef] [PubMed]
  96. Valavanidis, A.; Vlachogianni, T.; Fiotakis, K.; Loridas, S. Pulmonary Oxidative Stress, Inflammation and Cancer: Respirable Particulate Matter, Fibrous Dusts and Ozone as Major Causes of Lung Carcinogenesis through Reactive Oxygen Species Mechanisms. Int. J. Environ. Res. Public Health 2013, 10, 3886–3907. [Google Scholar] [CrossRef]
  97. Roszkowski, K.; Jozwicki, W.; Blaszczyk, P.; Mucha-Malecka, A.; Siomek, A. Oxidative damage DNA: 8-oxoGua and 8-oxodG as molecular markers of cancer. Med. Sci. Monit. 2011, 17, CR329–CR333. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Agha-Hosseini, F.; Mirzaii-Dizgah, I.; Farmanbar, N.; Abdollahi, M. Oxidative stress status and DNA damage in saliva of human subjects with oral lichen planus and oral squamous cell carcinoma. J. Oral Pathol. Med. 2012, 41, 736–740. [Google Scholar] [CrossRef]
  99. Korkmaz, K.S.; Butuner, B.D.; Roggenbuck, D. Detection of 8-OHdG as a diagnostic biomarker. J. Lab. Precis. Med. 2018, 3, 95. [Google Scholar] [CrossRef]
  100. Paredes-Sánchez, E.; Montiel-Company, J.M.; Iranzo-Cortés, J.E.; Almerich-Torres, T.; Bellot-Arcís, C.; Almerich-Silla, J.M. Meta-Analysis of the Use of 8-OHdG in Saliva as a Marker of Periodontal Disease. Dis. Markers 2018, 2018, 7916578. [Google Scholar] [CrossRef] [Green Version]
  101. Mascitti, M.; Togni, L.; Rubini, C.; Troiano, G.; Lo Muzio, L.; Santarelli, A. Tumour-associated tissue eosinophilia (TATE) in oral squamous cell carcinoma: A comprehensive review. Histol. Histopathol. 2021, 36, 113–122. [Google Scholar] [CrossRef]
  102. Troiano, G.; Rubini, C.; Togni, L.; Caponio, V.C.A.; Zhurakivska, K.; Santarelli, A.; Cirillo, N.; Lo Muzio, L.; Mascitti, M. The immune phenotype of tongue squamous cell carcinoma predicts early relapse and poor prognosis. Cancer Med. 2020, 9, 8333–8344. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Salivary microRNA related to diagnosis and prognosis of oral squamous cell cancer.
Table 1. Salivary microRNA related to diagnosis and prognosis of oral squamous cell cancer.
ReferenceBiomarkerFindingsClinical Relevance
[8,9,10,11,12]miRNA-24- miRNA 3P
miRNA412-3p miRNA 512-3p
miRNA302b-3p
miRNA 517b-3p
miRNA 134
miRNA 486-5p
miRNA 4484
miRNA 10b-5p
miRNA 200a
miRNA 365		Correlated with disease stage, histopathological type, and/or grade of OSCCPossible tool for the early diagnosis of OSCC; in general, the expression of these miRNAs indicates poor prognosis and higher risk of malignant transformation and oral cancer
[13,14,15,16,17,18,19,20]miRNA-27b
miRNA-200
miRNA-375
miRNA-26a
miRNA-7
miRNA-107
miRNA-218
miRNA let-7
miRNA-125		Tumor-suppressor roleIncreased levels of these biomarkers can be useful for the diagnosis, staging, and prognosis of OSCC; the expression of these miRNAs reduce the progession of OSCC
[1,21,22,23,24,25,26]miRNA-21
miRNA-145
miRNA-93
miRNA-184
miRNA-31
miRNA-412-3p
miRNA-34a		Tumor-activator role; these miRNAs acts as an oncogenes, promoting OSCC development and progressionElevated concentrations in the saliva offer a reliable method to detect OSCC and potentially malignant oral lesions
Table
Table 2. Salivary biomarkers related to diagnosis and prognosis of oral squamous cell cancer.
Table 2. Salivary biomarkers related to diagnosis and prognosis of oral squamous cell cancer.
ReferenceBiomarkerFindingsClinical Relevance
[38]IL-6, IL-8 & TNF-αNotably higher levels of these cytokines in advanced stages of OSCC compared to early stages of the disease;
presence of neck metastases associated with increased levels of these molecules.		Possible tool to indicate OSCC progression
[39]MMP-9Elevated salivary levels of MMP-9 were associated with OSCC
Levels of the biomarker decreased dramatically after tumor surgery		MMP-9 as a critical diagnostic and prognostic biomarker for OSCC
[40]IL-6, IL-8, IL-1β & TNF-αSignificant differences in levels of IL-6, IL-8, IL-1β, and TNF-α between OSCC patients and to controlsUseful complementary tool for the early detection of OSCC
[41]IL-8Significantly increased levels of the cytokine in patients with head and neck squamous cell carcinoma;
IL-8 levels were positively correlated with the abundance of C. albicans		A salivary microbial and inflammatory biomarker of head and neck squamous cell carcinoma that is influenced by oral health
[42]IL-6 & IL-8Correlation of qualitative salivary detection of IL-6 and IL-8 between control and disease groupsProbable biomarker for detection of premalignant lesions and OSCC
[43]IL-6 & TNF-αElevated levels of those cytokines compared to age-matched controlsIL-6 and TNF-α are potential biomarkers for the monitorization of OSCC
[44]MMP-9MMP-9 levels significantly higher in OSCC patients than in controls or patients with premalignant lesionsSalivary diagnostic biomarker for the detection of premalignant oral lesions and early stages of OSCC
[45]MMP-9Higher levels of MMP-9 in OSCC patients than in controlsMMP-9 is a good tool for the detection of OSCC
[46]IL-8Protein concentration of IL-8 was significantly elevated in patients with OSCC than in those with dysplasia and controlsImportant marker to discriminate between OSCC and control patients;
IL-8 combined with H3F3A mRNA provides good discrimination between OSCC and potentially malignant oral disorders
[47]IL-6, IL-8 & TNF-αIncreased levels of these cytokines in patients with oral leukoplakia, submucous fibrosis, and lichen planus than in healthy controlsDiagnostic tool for the detection of premalignant lesions
[48]IL-6Higher pretreatment levels of IL-6 in patients with oral cancer, associated with better survivalPossible prognosis biomarker
[49]IL-6Higher salivary levels of IL-6 in OSCC patients when compared with patients with chronic periodontitis, active oral lichen planus, inactive oral lichen planus, or healthy controlsUseful biomarker for the detection of OSCC
[50]TNF-αIncreased serum and saliva TNF-α levels in OSCC patients compared with controls and those with premalignant diseaseTNF-α as a useful biomarker for OSCC detection;
increased levels are associated with histological grade and clinical stage, suggesting a role in the prognosis of OSCC
[51]IL-6Increased levelsMonitoring of OSCC
[48]TNF-αNo differences between control and OSCC group-
[52]IL-6, IL-8 & TNF-αHigher levels in endophytic squamous cell carcinoma of the tongue than in exophytic squamous cell carcinoma of the tongue, correlated with decreased survival in the endophytic versus exophytic group;
IL-6, IL-8, and TNF-α also higher in the exophytic group than in smoking and drinking controls		These biomarkers can identify the progression of squamous cell carcinoma of the tongue from high risk to neoplasm;
important biomarker for cancer screening and early detection;
correlation between these proteins and survival implies a prognostic benefit potentially useful for management decisions and future target treatments
[53]IL-6 & IL-8Higher expression in patients with OSCCPotential tool for OSCC diagnosis
[54]IL-6, IL-8 & TNF-αIncreased levels in patients with OSCC and premalignant oral lesionsProangiogenic and proinflammatory cytokines are elevated in patients with these lesions;
diagnosis and prognosis significance of these markers
[55]IL-8 & IL-1βIncreased levels in patients with OSCCPotential use as a diagnostic tool for OSCC
[56]IL-8 & IL-1βHigher levels in OSCC patients, depending on the tumor stageIncreased levels of these biomarkers can be useful for OSCC diagnosis, staging, and prognosis
[57]IL-1βLevels significantly differ between before and after surgeryIL-1β levels may be useful for the detection of early stage OSCC
[58]IL-1-RaExpression of IL-1-Ra is lower in OSCC and oral dysplasia cells than in normal cellsPossible use as a biomarker for prediction of malignant transformation
[59]IL-1-RaExpression of IL-1-Ra decreases gradually with the progression of oral dysplasiaIL-1-Ra could be a reliable biomarker for the early diagnosis and follow-up of OSCC; it could be useful to discriminate between premalignant oral lesions and OSCC
[60]IL-1-Ra & IL-10Salivary IL-10 levels are higher in OSCC patients; IL-1-Ra levels are lower in well-defined tumors than in immature tumorsIL-10 is an interesting tool for diagnosing OSCC, and IL-1-Ra can be helpful for cancer staging
[61]IL-10High levels of IL-10 expression are found in OSCC, especially in advanced stage tumors and metastatic cellsSalivary IL-10 levels could be used as a biomarker for OSCC diagnosis; a high concentration appears to favor tumor proliferation and dissemination
[62]IL-10High levels of IL-10 expression correlate with shorter survival, worse prognosis, and increased risk of deathOverexpression of IL-10 is associated with aggressive forms of OSCC, and its level can be used as a survival predictor
[63]IL-10IL-10 levels increase with tumor progressionUseful as staging biomarker
[64]8-OHdG8-OHdG levels are approximately two-fold higher in patients with squamous head and neck cancer than in healthy controlsQuantification of 8-OHdG levels could be used as a diagnostic tool for OSCC
[65]8-OHdG8-OHdG levels are more than two-fold higher in in OSCC patients than in controls8-OHdG can be used as DNA damage biomarker to assess disease progression
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Manzano-Moreno, F.J.; Costela-Ruiz, V.J.; García-Recio, E.; Olmedo-Gaya, M.V.; Ruiz, C.; Reyes-Botella, C. Role of Salivary MicroRNA and Cytokines in the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma. Int. J. Mol. Sci. 2021, 22, 12215. https://doi.org/10.3390/ijms222212215

AMA Style

Manzano-Moreno FJ, Costela-Ruiz VJ, García-Recio E, Olmedo-Gaya MV, Ruiz C, Reyes-Botella C. Role of Salivary MicroRNA and Cytokines in the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma. International Journal of Molecular Sciences. 2021; 22(22):12215. https://doi.org/10.3390/ijms222212215

Chicago/Turabian Style

Manzano-Moreno, Francisco Javier, Victor J. Costela-Ruiz, Enrique García-Recio, Maria Victoria Olmedo-Gaya, Concepción Ruiz, and Candelaria Reyes-Botella. 2021. "Role of Salivary MicroRNA and Cytokines in the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma" International Journal of Molecular Sciences 22, no. 22: 12215. https://doi.org/10.3390/ijms222212215

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