miR-34a is downregulated and a regulator of drug resistance in prostate cancer (PCa). However, the mechanism of miR-34a in chemoresistance of PCa remains largely unknown. In the present study, we first confirmed the hypermethylation‑induced downregulation of miR-34a in PCa tissues and cell lines, PC-3 and DU145. Additionally, transfection of miR-34a mimics and demethylation by 5-azacytidine both resulted in the upregulation of miR-34a expression, which further induced declined cell proliferation and the enhanced apoptosis in PCa cells. Upregulation of miR-34a enhanced the chemosensitivity of PC-3 and DU145 cells. Furthermore, overexpression of miR-34a reduced the expression of autophagy-related proteins, ATG4B, Beclin-1 and LC3B II/I in PCa cells and demethylation treatment showed similar effect. ATG4B was confirmed directly by miR-34a targeting in PCa. Finally, downregulated p-AMPK and upregulated p-mTOR were detected in miR-34a overexpressed PCa cells. Collectively, miR-34a enhances chemosensitivity by directly downregulating ATG4B-induced autophagy through AMPK/mTOR pathway in PCa.

The aberrant expression of microRNAs (miRNAs/miRs) has been found in numerous cancer types. miR-32 is an oncomiR in prostate cancer (PCa), however, the mechanisms by which miR-32 functions as a regulator of radiotherapy response and resistance in PCa are largely unknown. In the present study, it was found that DAB2 interacting protein (DAB2IP), the miR-32-dependent tumor-suppressor gene, was downregulated and induced autophagy and inhibited radiotherapy-induced apoptosis in PCa cells. miR-32 expression was upregulated or overexpressed in PCa, and miR-32 inhibited DAB2IP expression through a direct binding site within the DAB2IP 3′ untranslated region. miR-32 mimics enhanced tumor cell survival and decreased radiosensitivity in the PCa cells, which were reversed by miR-32 inhibitor. Flow cytometric analysis revealed that overexpressed miR-32, consistent with the DAB2IP-knockdown results, reduced ionizing radiation (IR)-induced cell apoptosis, which was restored by 4 nM brefeldin A treatment. More significantly, the overexpression of miR-32 and the knockdown of DAB2IP enhanced autophagy in the IR-treated PCa cells. miR-32 regulated the expression of autophagy-related proteins, such as DAB2IP, Beclin 1 and Light chain 3β I/II, as well as phosphorylation of S6 kinase and mammalian target of rapamycin. In conclusion, these data provide novel insights into the mechanisms governing the regulation of DAB2IP expression by miR-32 and their possible contribution to autophagy and radioresistance in PCa.

HMGB1, which acts as a DNA chaperone to help maintain nuclear homeostasis, was reported to play a prominent role in cancer progression, angiogenesis, invasion, and metastasis development. Increased expression of HMGB1 has been observed in several tumor entities. However, the molecular mechanisms of HMGB1 in tumorigenesis of bladder cancer have rarely been reported. In the present study, real-time quantitative RT-PCR analysis revealed that the expression of HMGB1 in human bladder urothelial carcinoma (BUC) cells was much higher than that in human normal urethra epithelial cells. In order to investigate the role of HMGB1 in BUC cells, RNA interference and Talen-mediated gene knockout (KO) were used to knockdown and knockout HMGB1, respectively, in BUC cell lines BIU-87 and T24. HMGB1 knockdown/out greatly inhibited proliferation, invasion, and cell cycle G1/S transition of BUC cells. The decrease in cell viability caused by HMGB1 knockdown/out was due to an increase in apoptosis via Bax/Bcl-2, both of which were important molecules involved in the apoptotic pathway. We then investigated the effect of HMGB1 knockdown/out on the sensitivity of BUC cells treated with the anticancer drug cisplatin. Knockdown or knockout of HMGB1 rendered BUC cells more sensitive to cisplatin. The decreased expression of LC3-II and Beclin 1, which resulted in decreased levels of autophagy, could probably explain this phenomenon. Thus, HMGB1 may become a novel promising candidate for the prognosis and therapy for bladder cancer.

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