Regulatory Role of mir-203 in Prostate Cancer Progression and Metastasis

Abstract

Purpose: Advanced metastatic prostate cancer (PCa) is a fatal disease, with only palliative therapeutic options. Though almost 80% of cases of metastatic PCa present bone metastasis, our current understanding of the molecular mechanisms that govern this metastatic dissemination remains fragmentary. The main objective of the present study was to identify microRNA (miRNA) genes that regulate metastatic PCa.Experimental Design: miRNA expression profiling was done in human prostate cell lines to identify dysregulated miRNA components of advanced PCa. miR-203 expression was assessed in prostate carcinoma cell lines and clinical specimens by real-time PCR and in situ hybridization. To assess the biological significance of miR-203, miR-203 was reexpressed in bone metastatic PCa cell lines followed by in vitro and in vivo functional assays.Results: miR-203 expression is specifically attenuated in bone metastatic PCa suggesting a fundamental antimetastatic role for this miRNA. Reintroduction of miR-203 in bone metastatic PCa cell lines suppresses metastasis via inhibition of several critical steps of the metastatic cascade including epithelial-mesenchymal transition, invasion, and motility. Ectopic miR-203 significantly attenuated the development of metastasis in a bone metastatic model of PCa. Importantly, miR-203 regulates a cohort of pro-metastatic genes including ZEB2, Bmi, survivin, and bone-specific effectors including Runx2, a master regulator of bone metastasis.Conclusions: miR-203 is an "antimetastatic" miRNA in PCa that acts at multiple steps of the PCa metastatic cascade via repression of a cohort of prometastatic targets. miR-203 may be an attractive target for therapeutic intervention in advanced PCa.

Diagnostic value of microRNAs in prostate cancer patients with prostate specific antigen (PSA) levels between 2, and 10 ng/mL

“…[30] In a study where miR-203 (new nomenclature: miR-203a) expressions in malign, and normal prostate tissue were compared, decrease in miR-203 expression was demonstrated in correlation with advanced PCa, and its"anti-metastatic" value was suggested. [35] Also in our study, in compliance with the literature decrease in miR-203 levels was observed.…”

MicroRNAs in prostate cancer: from biomarkers to molecularly-based therapeutics

“…Zhang et al 47 observed that miR-17-3p regulates the expression of vimentin and altered expression of miR-17-3p decreases the tumorigenic behavior and reduces tumor size in nude mice. Saini et al 51 also noted that relative miR-203 expression is lower in prostate cancer cell lines derived from bone metastasis, and over-expression of miR-203 has a negative effect on the development of metastases in nude mice. Significantly, miR-203 has been shown to repress bone-specific transcriptional regulators, such as Runx2 and Dlx5, in addition to regulating pro-metastatic genes ZEB2, Bmi and Survivin.…”

MicroRNAs in liver cancer: a model for investigating pathogenesis and novel therapeutic approaches

“…47 Apoptosis is also controlled by molecules not belonging to the BCL2 family. For example, the inhibitor of apoptosis protein (IAP), survivin, is overexpressed in HCC and is controlled by miR-203, 48 a miRNA silenced by aberrant DNA methylation in HCC tissue. 23 Another miRNA, miR-21, appears to promote cell survival under stressful conditions.…”