Role of MicroRNAs in Neuroendocrine Prostate Cancer

Therapy-induced neuroendocrine prostate cancer (t-NEPC/NEPC) is an aggressive variant of prostate cancer (PCa) that frequently emerges in castration-resistant prostate cancer (CRPC) under the selective pressure of androgen receptor (AR)-targeted therapies. This variant is extremely aggressive, metastasizes to visceral organs, tissues, and bones despite low serum PSA, and is associated with poor survival rates. It arises via a reversible trans-differentiation process, referred to as ‘neuroendocrine differentiation’ (NED), wherein PCa cells undergo a lineage switch and exhibit neuroendocrine features, characterized by the expression of neuronal markers such as enolase 2 (ENO2), chromogranin A (CHGA), and synaptophysin (SYP). The molecular and cellular mechanisms underlying NED in PCa are complex and not clearly understood, which contributes to a lack of effective molecular biomarkers for diagnosis and therapy of this variant. NEPC is thought to derive from prostate adenocarcinomas by clonal evolution. A characteristic set of genetic alterations, such as dual loss of retinoblastoma (RB1) and tumor protein (TP53) tumor suppressor genes and amplifications of Aurora kinase A (AURKA), NMYC, and EZH2, has been reported to drive NEPC. Recent evidence suggests that microRNAs (miRNAs) are important epigenetic players in driving NED in advanced PCa. In this review, we highlight the role of miRNAs in NEPC. These studies emphasize the diverse role that miRNAs play as oncogenes and tumor suppressors in driving NEPC. These studies have unveiled the important role of cellular processes such as the EMT and cancer stemness in determining NED in PCa. Furthermore, miRNAs are involved in intercellular communication between tumor cells and stromal cells via extracellular vesicles/exosomes that contribute to lineage switching. Recent studies support the promising potential of miRNAs as novel diagnostic biomarkers and therapeutic targets for NEPC.