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Abstract：
Bladder cancer (BC) cells exhibit a high basal level of autophagy activity, which contributes to the development of a protective mechanism for cellular survival against current treatments. Hsa‑microRNA‑34a (miR‑34a) presents anti‑tumor function in several types of cancer. However, the functional mechanism of miR‑34a in regulating tumor aggressiveness and protective autophagy of BC remains largely unknown. First, transfected BC cells with miR‑34a mimic exhibited LC3‑II and p62 accumulation through immunofluorescence staining. It was demonstrated that syntaxin 17 (STX17), which is required for autophagosome‑lysosome fusion, was downregulated upon miR‑34a mimic treatment. Mechanistically, miR‑34a reduced the expression of STX17 proteins that directly bind on STX17 3\'‑untranslated regions and thus suppressed STX17 mRNA translation to eventually inhibit protective autophagy in BC. Cell viability and colony formation assays revealed that overexpression of miR‑34a in BC cells enhances the chemosensitivity of cisplatin, doxorubicin, epirubicin and mitomycin C. Furthermore, miR‑34a inhibited cell proliferation and triggered G0/G1 cell cycle arrest by inhibiting cyclin D1 and cyclin E2 protein expression. Moreover, miR‑34a suppressed cell motility through the downregulation of epithelial‑mesenchymal transition. In summary, miR‑34a inhibits cell proliferation, motility and autophagy activity in BC, which can benefit BC treatment.
摘要：
膀胱癌（BC）细胞表现出较高的基础水平的自噬活性，这有助于开发针对当前治疗的细胞存活的保护机制。Hsa-microRNA-34a（miR-34a）在几种类型的癌症中具有抗肿瘤功能。然而,miR‑34a在调节BC肿瘤侵袭性和保护性自噬方面的功能机制仍不清楚.首先,用miR‑34a模拟物转染的BC细胞通过免疫荧光染色显示LC3‑II和p62积累。研究表明，语法蛋白17(STX17)，这是自噬体-溶酶体融合所必需的，在miR‑34a模拟治疗后下调。机械上,miR-34a降低直接结合STX173''-非翻译区的STX17蛋白的表达，从而抑制STX17mRNA翻译，最终抑制BC中的保护性自噬。细胞活力和集落形成分析显示，miR-34a在BC细胞中的过表达增强了顺铂的化学敏感性，阿霉素,表柔比星和丝裂霉素C。此外，miR‑34a通过抑制细胞周期蛋白D1和细胞周期蛋白E2蛋白表达来抑制细胞增殖并触发G0/G1细胞周期阻滞。此外，miR‑34a通过下调上皮间质转化抑制细胞运动。总之,miR‑34a抑制细胞增殖，BC的运动性和自噬活性，这可以使BC治疗受益。
