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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.

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. [ABSTRACT FROM AUTHOR]

Interleukin-1 receptor-associated kinase-3 (IRAK3) has a distinctive role in regulating inflammation. However, the functional role of IRAK3 and regulatory mechanism underlying the pathogenesis of osteoarthritis (OA) remain unclear. Here, we first found that IRAK3 was upregulated, while miR-33b-3p was downregulated in the cartilage of OA patients and IL-1β-induced CHON-001 cells. IRAK3 was confirmed as the direct target of miR-33b-3p and negatively regulated by miR-33b-3p. There was an inverse correlation between IRAK3 mRNA expression and miR-33b-3p expression in OA cartilage tissues. The in vitro functional experiments showed that miR-33b-3p overexpression caused a remarkable increase in viability, a significant decrease in inflammatory mediators (IL-1β and TNF-α), and apoptosis in IL-1β-induced CHON-001 cells. Importantly, IRAK3 knockdown imitated, while overexpression reversed the effects of miR-33b-3p on IL-1β-induced inflammation and apoptosis in CHON-001 cells. Collectively, miR-33b-3p significantly alleviated IL-1β-induced inflammation and apoptosis by downregulating IRAK3, which may serve as a promising target for OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a common and frequently-occurring disease in middle-aged and older people. A growing number of studies have shown that microRNAs (miRNAs) are involved in the development of OA. However, the role and mechanism of miR-33b-3p in OA remain ill-defined. The levels of miR-33b-3p and DNA methyltransferase 3A (DNMT3A) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). The levels of DNMT3A protein, matrix metalloprotein 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5), collagen II, aggrecan, cleaved Caspase-3, B-cell lymphoma-2 (Bcl-2) and BCL2-Associated X (Bax) were measured by Western blot assay. Cell proliferation and cell apoptosis were assessed by Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, respectively. The targeting relationship between miR-33b-3p and DNMT3A was verified by dual-luciferase reporter assay. The expression of miR-33b-3p was decreased and the expression of DNMT3A was increased in OA cartilage tissues and IL-1β-induced chondrocytes. There was an inverse correlation between miR-33b-3p and DNMT3A in OA cartilage tissues. MiR-33b-3p overexpression or DNMT3A knockdown inhibited extracellular matrix (ECM) degradation and cell apoptosis and promoted cell proliferation in IL-1β-induced chondrocytes. Moreover, DNMT3A was confirmed to be a direct target of miR-33b-3p. Upregulation of DNMT3A weakened the effects of miR-33b-3p overexpression on cartilage ECM degradation, cell proliferation and apoptosis in IL-1β-activated chondrocytes. MiR-33b-3p overexpression suppressed cartilage ECM degradation and cell apoptosis, and promoted cell proliferation by directly targeting DNMT3A in IL-1β-stimulated chondrocytes. • MiR-33b-3p and DNMT3A were dysregulated in OA cartilage tissues and IL-1β-induced chondrocytes. • MiR-33b-3p promoted cell proliferation and inhibited cartilage ECM degradation and cell apoptosis. • DNMT3A knockdown showed the same effects with miR-33b-3p on cartilage ECM degradation, cell proliferation and apoptosis. • DNMT3A was a direct target of miR-33b-3p. • MiR-33b-3p regulated cartilage ECM degradation, cell proliferation and apoptosis by targeting DNMT3A. [ABSTRACT FROM AUTHOR]