The role of miRNAs as biomarkers in prostate cancer

Abstract

There is an urged need of non-invasive biomarkers for the implementation of precision medicine. These biomarkers are required to these days for improving prostate cancer (PCa) screening, treatment or stratification in current clinical strategies. There are several commercial kits (Oncotype DX genomic prostate score^®, Prolaris^®, among others) that use genomic changes, rearrangement or even non-coding RNA events. However, none of them are currently used in the routine clinical practice. Many recent studies indicate that miRNAs are relevant molecules (small single-stranded non-coding RNAs that regulate gene expression of more than 30% of human genes) to be implement non-invasive biomarkers. However, contrasting to others tumors, such as breast cancer where miR-21 seems to be consistently upregulated; PCa data are controversial. Here we reported an extended revision about the role of miRNAs in PCa including data of AR signaling, cell cycle, EMT process, CSCs regulation and even the role of miRNAs as PCa diagnostic, prognostic and predictive tool. It is known that current biomedical research uses big-data analysis like Next Generation Sequencing (NGS) analysis. We also conducted an extensive online search, including the main platforms and kits for miRNAs massive analysis (like MiSeq, Nextseq 550, or Ion S5™ systems) indicating their pros, cons and including pre-analytical and analytical issues of miRNA studies.

Introduction

Prostate cancer (PCa) is the second most common cancer among men, with a rate of 1.1 million of new cases diagnosed in 2012 [1]. There are several clinical criteria used as screening or stratification parameters such as prostate specific antigen (PSA) value, imaging diagnostics and histopathological scores (e.g. Gleason score), however these ones are not efficient as prognosis biomarkers. Currently there are some prognostic commercial biomarkers, such as Oncotype DX genomic prostate score® (Genomic health, CA, USA), Prolaris® (Myriad Genetics Inc., UT, USA), ProMark® (Metamark, MA, USA), ExoDx™ Prostate (IntelliScore, MA, USA) or Decipher® (GenomeDX, Vancouver, Canada), among others, all based on several SNPs panels or epigenetic modifications; but none of them show accurate data [2]. Some molecular biomarkers are in use, such as prostate cancer gene 3 (PCA3 or DD3) detected in urine and based on specific PCa tissue non-coding RNA, and which is currently included in the European Association of Urology (EAU) guidelines as a factor for biopsy decision making. TMPRSS2:ERG fusion transcripts are also reported as urine biomarkers that seems to be indicative of PCa aggressiveness upon biopsy. Mainly PCA3 but also TMPRSS2:ERG are considered with a valuable potential in PSA quandary situations. It is also suggested that the combination of PCA3 with TMPRSS2:ERG fusion transcripts could improve the specificity and sensitivity compared to the single use of these both non-invasive markers [3].

The main aim of current medicine is to develop efficient and non-invasive biomarkers. Most of promising PCa biomarkers are developed in urine, such as ExoDx™ Prostate (Intelliscore, MA, USA) which uses exosomal RNA for reducing the rate of unnecessary biopsies [4]; or previous described PCA3 and TMPRSS2:ERG. But it is true that there are also a high proportion of biomarkers used in tissue such as Oncotype DX genomic prostate score® (Genomic health, CA, USA), Prolaris® (Myriad Genetics Inc., UT, USA), and ProMark® (Metamark, MA, USA); used for monitoring the aggressiveness of the tumor. Moreover Decipher® (GenomeDX, Vancouver, Canada) is also detected in tissue sample but mainly focused in monitoring treatment course after prostate surgery. See more details in Supplementary Table 1.

Concerning miRNAs, miRview™mets (Rosetta Genomics, PA, USA) was the first miRNA-based cancer diagnostic available test. This test studies a 48-panel of miRNAs in tissue for 22 tumor types to determine the origin of metastasis. A second-generation test (miRview mets²), increases the number of tumor types to 49 based in a 64 miRNAs panel [5]. However, up to now there is any test based on miRNAs for the diagnosis or prognosis of primary PCa.

The development of advanced high-throughput ‘omics’ technologies has enabled the use of novel and more efficient markers guiding the prognosis and improving PCa treatment´s strategies. Currently, there are numerous molecular markers used with this aim, mainly focused on the mechanisms of castration resistance, trying to offer the best treatment opportunities. The main molecular markers are focused on: i) androgen receptor (AR) mutations, overexpression, or splice variants; ii) CYP17 variants; or iii) PARP (Poly (ADP-ribose) Polymerases) inhibitors which are the molecular targets of several treatments such as bicalutamide, flutamide, enzalutamide, abiraterone, docetaxel or cabazitaxel [6].

Among future predictive biomarkers those ones based on liquid biopsy components such as circulating tumor cells (CTCs) or free nucleic acids should also be mentioned. Here, we are focusing on the role of miRNAs, mainly in their use as cancer biomarkers. It is well known the role of miRNAs modulating important cellular cancer processes/pathways and their stability in body fluids; they are points that make these molecules as promising biomarkers.

Moreover, there are data suggesting their diagnostic (miR-21and miR-141) [7] and prognosis role (miR-141 and miR-375) in PCa [8]. All previous mentioned miRNAs characteristics suggest that these biomolecules could improve the current limitations existing in commercial panels; mainly due to their broad molecular activities and their non-invasiveness option of study. The goal of the present review is to determine the most important roles and limitations of miRNAs as biomarkers for PCa in current medicine.