MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib
MiRNA-30a-mediated autophagy inhibition sensitizes renal cell carcinoma cells to sorafenib
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DOI：
10.1016/j.bbrc.2015.02.084
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发表时间：
2015-04-03
影响因子：
3.1
通讯作者：
Shan, Yuxi
中科院分区：
文献类型：
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作者：
Zheng, Bing;Zhu, Hua;Shan, Yuxi
化疗诱导的自噬激活通常有助于癌症抵抗。 MiRNA-30a (miR-30a) 是一种通过下调 Beclin-1 来有效抑制自噬的抑制剂。在这项研究中，我们表征了 miR-30a 在索拉非尼诱导的肾细胞癌 (RCC) 细胞活性中的作用。我们发现 miR-30a 的表达在几种人 RCC 组织和 RCC 细胞系中显着下调。因此，其靶基因Beclin-1被上调。索拉非尼在 RCC 细胞（786-0 和 A489 系）中激活自噬，p62 降解、Beclin-1/自噬蛋白 5 (ATG-5) 上调和轻链 (LC)3B-1/II 转换证明了这一点。在 786-0 或 A489 细胞中外源表达 miR-30a 可抑制 Beclin-1 表达并增强索拉非尼诱导的细胞毒性。相反，通过引入antagomiR-30a来敲低miR-30a会增加Beclin-1的表达，并抑制索拉非尼诱导的针对RCC细胞的细胞毒性。自噬抑制剂，包括氯喹、3-甲基腺嘌呤或巴夫霉素 A1，增强索拉非尼活性，导致大量细胞凋亡。同时，通过靶向siRNA敲低Beclin-1或ATG-5也增加了索拉非尼在上述RCC细胞中诱导的细胞毒性。这些发现表明，RCC 中 miR-30a 的失调可能会通过自噬依赖性途径干扰索拉非尼介导的细胞凋亡的有效性，从而成为 RCC 的新的潜在治疗靶点。 (C) 2015 Elsevier Inc. 保留所有权利。
Chemotherapy-induced autophagy activation often contributes to cancer resistance. MiRNA-30a (miR-30a) is a potent inhibitor of autophagy by downregulating Beclin-1. In this study, we characterized the role of miR-30a in sorafenib-induced activity in renal cell carcinoma (RCC) cells. We found that expression of miR-30a was significantly downregulated in several human RCC tissues and in RCC cell lines. Accordingly, its targeted gene Beclin-1 was upregulated. Sorafenib activated autophagy in RCC cells (786-0 and A489 lines), evidenced by p62 degradation, Beclin-l/autophagy protein 5 (ATG-5) upregulation and light chain (LC)3B-l/II conversion. Exogenously expressing miR-30a in 786-0 or A489 cells inhibited Beclin-1 expression and enhanced sorafenib-induced cytotoxicity. In contrast, knockdown of miR-30a by introducing antagomiR-30a increased Beclin-1 expression, and inhibited sorafenib-induced cytotoxicity against RCC cells. Autophagy inhibitors, including chloroquine, 3-methyaldenine or Bafliomycin A1, enhanced sorafenib activity, causing substantial cell apoptosis. Meanwhile, knockdown of Beclin-1 or ATG-5 by targeted siRNAs also increased sorafenib-induced cytotoxicity in above RCC cells. These findings indicate that dysregulation of miR-30a in RCC may interfere with the effectiveness of sorafenib-mediated apoptosis by an autophagy-dependent pathway, thus representing a novel potential therapeutic target for RCC. (C) 2015 Elsevier Inc. All rights reserved.