Abstract
Prostate cancer is a condition commonly associated with men worldwide. Androgen deprivation therapy remains one of the targeted therapies. However, after some years, there is biochemical recurrence and metastatic progression into castration-resistant prostate cancer (CRPC). CRPC cases are treated with second-line androgen deprivation therapy, after which, these CRPCs transdifferentiate to form neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. NEPC arises via a reversible transdifferentiation process, known as neuroendocrine differentiation (NED), which is associated with altered expression of lineage markers such as decreased expression of androgen receptor and increased expression of neuroendocrine lineage markers including enolase 2, chromogranin A and synaptophysin. The etiological factors and molecular basis for NED are poorly understood, contributing to a lack of adequate molecular biomarkers for its diagnosis and therapy. Therefore, there is a need to fully understand the underlying molecular basis for this cancer. Recent studies have shown that microRNAs (miRNAs) play a key epigenetic role in driving therapy-induced NED in prostate cancer. In this review, we briefly describe the role of miRNAs in prostate cancer and CRPCs, discuss some key players in NEPCs and elaborate on miRNA dysregulation as a key epigenetic process that accompanies therapy-induced NED in metastatic CRPC. This understanding will contribute to better clinical management of the disease.
Highlights
Prostate cancer (PCa) remains the second leading cause of cancer death in men after lung cancer, according to the American Cancer Society[1]
The disease declines in most patients for some time, but progresses to castration-resistant prostate cancer (CRPC), which does not respond to hormonal therapy[7]
neuroendocrine prostate cancer (NEPC) arises via a reversible transdifferentiation process, known as neuroendocrine differentiation (NED), which is associated with altered expression of lineage markers such as decreased expression of androgen receptor (AR) and increased expression of neuroendocrine (NE) lineage markers including enolase 2 (ENO2), chromogranin A (CHGA) and synaptophysin (SYP)[13,14]
Summary
Prostate cancer (PCa) remains the second leading cause of cancer death in men after lung cancer, according to the American Cancer Society[1]. Their data showed that AI LNCaP cells expressed 5-fold increased levels of miR-125b when compared with the androgen-dependent parental LNCaP cells This suggests that miRNA-125b may contribute to castration resistance and further progression to NEPC by enhancing androgen independent growth. A significant number of studies suggest an important role of miRNAs as biomarkers for detection and prognosis in the management of PCa, especially the NE variant[126,127] Some of these miRNAs have been shown to be a novel therapeutic target in the treatment of advanced forms of PCa. miR-15a and miR-16 which act as tumor suppressors by targeting CCND1, WNT3A and Bcl may be considered to have therapeutic potential in NEPC by either acting independently or being used as a combinational therapy with chemotherapy[86]. Due to the fact that miRNAs can target myriad genes, there is a problem of off-target effects which can be lethal to non-targeted cells[138,139,140]
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