Abstract
Despite that androgen-deprivation therapy results in long-lasting responses, the disease inevitably progresses to metastatic castration-resistant prostate cancer. In this study, we identified miR-33b-3p as a tumor suppressor in prostate cancer. miR-33b-3p was significantly reduced in prostate cancer tissues, and the low expression of miR-33b-3p was correlated with poor overall survival of prostate cancer patients. Overexpression of miR-33b-3p inhibited both migration and invasion of highly metastatic prostate cancer cells whereas inhibition of miR-33b-3p promoted those processes in lowly metastatic cells. The in vivo results demonstrate that miR-33b-3p suppresses metastasis of tail vein inoculated prostate cancer cells to lung and lymph nodes in mice. DOCK4 was validated as the direct target of miR-33b-3p. miR-33b-3p decreased the expression of DOCK4 and restoration of DOCK4 could rescue miR-33b-3p inhibition on cell migration and invasion. Moreover, downregulation of miR-33b-3p was induced by bortezomib, the clinically used proteasome inhibitor, and overexpression of miR-33b-3p enhanced the insufficient inhibition of bortezomib on migration and invasion as well as metastasis of prostate cancer cells. In summary, our findings demonstrate that miR-33b-3p suppresses metastasis by targeting DOCK4 in prostate cancer. Our results suggest that enhancing miR-33b-3p expression may provide a promising therapeutic strategy for overcoming that proteasome inhibitor’s poor efficacy against metastatic prostate cancer.
Highlights
Prostate cancer is the most common malignancies and the second leading cause of cancerassociated mortality in men [1]
We found that miR-33b-3p was the dominant mature form in prostate cancer
To investigate the role of miR-33b-3p in migration and invasion of prostate cancer cells, the PC-3M-1E8 and PC-3M2B4 cell lines that are derived from PC-3M prostate cancer cells but with different metastatic potentials were used as cell models [26]
Summary
Prostate cancer is the most common malignancies and the second leading cause of cancerassociated mortality in men [1]. Despite that androgen-deprivation therapy results in longlasting responses, the disease inevitably progresses to metastatic castration-resistant prostate cancer (mCRPC) that is associated with poor prognosis [2, 3]. The proteasome is a validated miR-33b-3p Suppresses Prostate Cancer Metastasis target for cancer therapy. The first-in-class proteasome inhibitor bortezomib demonstrates great success against multiple myeloma [4]. Limited efficacy of bortezomib alone was observed in solid tumors including prostate cancer. Bortezomib was found not able to improve prostate cancer patients’ response to docetaxel, a standard treatment for mCRPC [5, 6]
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