Abstract
Prostate cancer is the second leading cause of cancer-related deaths of men in the Western world. Despite recent advancement in genomics, transcriptomics and proteomics to understand prostate cancer biology and disease progression, castration resistant metastatic prostate cancer remains a major clinical challenge and often becomes incurable. MicroRNAs (miRNAs), about 22-nucleotide-long non-coding RNAs, are a group of regulatory molecules that mainly work through post-transcriptional gene silencing via translational repression. Expression analysis studies have revealed that miRNAs are aberrantly expressed in cancers and have been recognized as regulators of prostate cancer progression. In this critical review, we provide an analysis of reported miRNA functions and conflicting studies as they relate to expression levels of specific miRNAs and prostate cancer progression; oncogenic and/or tumor suppressor roles; androgen receptor signaling; epithelial plasticity; and the current status of diagnostic and therapeutic applications. This review focuses on select miRNAs, highly expressed in normal and cancer tissue, to emphasize the current obstacles faced in utilizing miRNA data for significant impacts on prostate cancer therapeutics.
Highlights
Accurate gene expression control is important for the formation, maintenance and repair of complex biological structures
Failure to respond to androgen receptor (AR)-centered therapy and development of castration-resistant prostate cancer (CRPC) is associated with diverse molecular mechanisms applied by prostate cancer cells [164]
The majority of differentially expressed miRNAs in prostate cancer are progressively down-regulated in their expression during tumor progression, as has been reviewed previously [59]
Summary
Accurate gene expression control is important for the formation, maintenance and repair of complex biological structures. A dichotomy of miRNAs, consisting of an “inactive” LMW form (with unclear but putative anti-viral functions) and an “active” HMW-form in growing cells, is reflected in the Dgrc knockout mouse prostate such that there is an absence of an obvious phenotype under normal conditions, but the presence of a strong phenotype upon tissue activation and tumorigenesis [4]. There seems to be no clear miRNA signature that may distinguish normal prostate from cancer, at least when looking for consensus in the literature (“Any miRNA-based clinical screening still lacks a consensus signature to be applied in the routine assay, and needs further validation in an intended use population” [15]) In contrast to these ambiguous reports on individual miRNAs in prostate biology, the effect of ablation of Dicer suggests an important role of miRNAs in general in the prostate [16]. Regardless of whether miRNAs are truly significant for prostate formation and maintenance, their requirement for mouse prostate tumorigenesis in a Pten knock out tumor model has been well documented [4]
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