Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance

Abstract

Prostate cancer (PCa) mortality remains a significant public health problem, as advanced disease has poor survivability due to the development of resistance in response to both standard and novel therapeutic interventions. Therapeutic resistance is a multifaceted problem involving the interplay of a number of biological mechanisms including genetic, signaling, and phenotypic alterations, compounded by the contributions of a tumor microenvironment that supports tumor growth, invasiveness, and metastasis. The androgen receptor (AR) is a primary regulator of prostate cell growth, response and maintenance, and the target of most standard PCa therapies designed to inhibit AR from interacting with androgens, its native ligands. As such, AR remains the main driver of therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). While androgen deprivation therapy (ADT), in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in patients with mCRPC, therapeutic resistance invariably develops, leading to lethal disease. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes and also to the development of biomarker signatures of predictive value. The interconversions between epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) navigate the prostate tumor therapeutic response, and provide a novel targeting platform in overcoming therapeutic resistance. Both microRNA (miRNA)- and long non-coding RNA (lncRNA)-mediated mechanisms have been associated with epigenetic changes in prostate cancer. This review discusses the current evidence-based knowledge of the role of the phenotypic transitions and novel molecular determinants (non-coding RNAs) as contributors to the emergence of therapeutic resistance and metastasis and their integrated predictive value in prostate cancer progression to advanced disease.

Keywords: EMT; NEPC; anoikis; lncRNA; metastasis; miRNA; ncRNA; therapeutic resistance.

Figure 1

microRNA (miRNA) Regulation of Epithelial-to-Mesenchymal Transition (EMT) in Cancer. Over 30 different miRNAs are now known to interact with EMT-related signaling effectors in prostate cancer. This schema reveals the critical miRNAs that negatively regulate EMT, via inhibition of SNAIL, SLUG, ZEB1/2, TWIST and TGF-β. Regulation of EMT is complex, as miRNAs can have multiple targets (miR-299, miR15a/16) or are themselves regulated by EMT components in a feedback loop (miR-1/miR-200b and SLUG). The process of EMT involves the cellular transformation from an epithelial phenotype to a mesenchymal one in preparation for metastasis. Utilizing miRNAs and other non-coding RNAs (ncRNAs) to regulate EMT interconversion to mesenchymal-to-epithelial transition (MET) in order to impair metastasis could be a novel therapeutic strategy to treat advanced or resistant prostate cancer.