MicroRNA-34a, Prostate Cancer Stem Cells, and Therapeutic Development

SIMPLE SUMMARY: Prostate cancer is still the most common cancer among men in the US. Current standard-of-care therapies for metastatic castration-resistant prostate cancer can offer survival benefits measured only in months. The patients eventually develop drug resistance and tumor relapse. There is strong evidence that during treatment, prostate cancer stem cells may become the predominant population within tumor bulk, and function as the “root cause” for drug resistance. microRNA-34a, a bona fide tumor-suppressive miRNA, represents a potent cancer stem cell suppressor by targeting many molecules essential for cancer stem cell survival. This article will review the tumor suppressive role of miRNA-34a in prostate cancer, and its therapeutic development strategies for advanced prostate cancer patients. ABSTRACT: Prostate cancer (PCa) is a highly heterogeneous disease and typically presents with multiple distinct cancer foci. Heterogeneity in androgen receptor (AR) expression levels in PCa has been observed for decades, from untreated tumors to castration-resistant prostate cancer (CRPC) to disseminated metastases. Current standard-of-care therapies for metastatic CRPC can only extend life by a few months. Cancer stem cells (CSCs) are defined as a subpopulation of cancer cells that exists in almost all treatment-naive tumors. Additionally, non-CSCs may undergo cellular plasticity to be reprogrammed to prostate cancer stem cells (PCSCs) during spontaneous tumor progression or upon therapeutic treatments. Consequently, PCSCs may become the predominant population in treatment-resistant tumors, and the “root cause” for drug resistance. microRNA-34a (miR-34a) is a bona fide tumor-suppressive miRNA, and its expression is dysregulated in PCa. Importantly, miR-34a functions as a potent CSC suppressor by targeting many molecules essential for CSC survival and functions, which makes it a promising anti-PCSC therapeutic. Here, we conducted a comprehensive literature survey of miR-34a in the context of PCa and especially PCSCs. We provided an updated overview on the mechanisms of miR-34a regulation followed by discussing its tumor suppressive functions in PCa. Finally, based on current advances in miR-34a preclinical studies in PCa, we offered potential delivery strategies for miR-34a-based therapeutics for treating advanced PCa.