Deregulated microRNAs Involved in Prostate Cancer Aggressiveness and Treatment Resistance Mechanisms

SIMPLE SUMMARY: Accumulating studies have highlighted the critical roles of microRNAs in tumorigenesis and cancer treatment responses. Here, we systematically review the scientific publications describing the roles of microRNAs in the development and progression of prostate cancer. Numerous studies have demonstrated that microRNAs target and regulate critical genes involved in prostate cancer aggressiveness and drug resistance. However, the molecular mechanisms underlying microRNA involvement in the advanced and treatment-resistant prostate cancers remain unclear. This review aims to highlight the current understanding and knowledge gap related to the deregulation of microRNAs in prostate cancer diseases. Furthermore, we summarize the promising progress on the development of microRNA-based diagnostic/prognostic biomarkers and therapies for prostate cancer. ABSTRACT: Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer deaths among American men. Complex genetic and epigenetic mechanisms are involved in the development and progression of PCa. MicroRNAs (miRNAs) are short noncoding RNAs that regulate protein expression at the post-transcriptional level by targeting mRNAs for degradation or inhibiting protein translation. In the past two decades, the field of miRNA research has rapidly expanded, and emerging evidence has revealed miRNA dysfunction to be an important epigenetic mechanism underlying a wide range of diseases, including cancers. This review article focuses on understanding the functional roles and molecular mechanisms of deregulated miRNAs in PCa aggressiveness and drug resistance based on the existing literature. Specifically, the miRNAs differentially expressed (upregulated or downregulated) in PCa vs. normal tissues, advanced vs. low-grade PCa, and treatment-responsive vs. non-responsive PCa are discussed. In particular, the oncogenic and tumor-suppressive miRNAs involved in the regulation of (1) the synthesis of the androgen receptor (AR) and its AR-V7 splice variant, (2) PTEN expression and PTEN-mediated signaling, (3) RNA splicing mechanisms, (4) chemo- and hormone-therapy resistance, and (5) racial disparities in PCa are discussed and summarized. We further provide an overview of the current advances and challenges of miRNA-based biomarkers and therapeutics in clinical practice for PCa diagnosis/prognosis and treatment.