MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways
MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways
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MicroRNA-122通过靶向IGF-1R调节RAS/RAF/ERK信号通路赋予索拉非尼对肝细胞癌细胞的耐药性
DOI：
10.1016/j.canlet.2015.11.034
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发表时间：
2016-01-01
期刊：
影响因子：
9.7
通讯作者：
Qian, Cheng
中科院分区：
文献类型：
--
作者：
Xu, Yanmin;Huang, Ji;Qian, Cheng
索拉非尼是晚期肝细胞癌（HCC）的一线治疗药物，但索拉非尼的临床反应受到耐药性的严重限制。在这项研究中，我们研究了肝癌细胞中索拉非尼耐药的分子机制。我们的 miRNA 微阵列数据表明，索拉非尼耐药细胞中肝脏特异性 miR-122 表达显着降低。 miR-122的过度表达使耐药细胞对索拉非尼敏感并诱导细胞凋亡。胰岛素样生长因子 1 受体 (IGF-1R) 被验证为 miR-122 的靶标，并被该 miRNA 抑制。 miR-122 诱导的细胞凋亡被 IGF-1R 激活剂 IGFI 或 IGFII 抑制。相反，IGF-1R抑制剂PPP或NVP-AEW541与索拉非尼联合显着诱导细胞凋亡并破坏体外药物耐受性。这些结果表明，通过异位下调 miR-122 激活 IGF-1R 抵消了索拉非尼诱导的细胞凋亡的影响，从而赋予索拉非尼耐药性。进一步的研究表明，miR-122下调激活IGF-1R有助于激活RAS/RAF/ERK信号传导，这与耐药性相关。我们的数据表明 miR-122 和 IGF-1R 异常表达之间的密切相关性是索拉非尼耐受的关键决定因素。 (C) 2015 Elsevier Ireland Ltd. 保留所有权利。
Sorafenib is the first-line treatment for advanced hepatocellular carcinoma (HCC), but the clinical response to sorafenib is seriously limited by drug resistance. In this study, we investigated the molecular mechanisms of sorafenib resistance in HCC cells. Our miRNA microarray data indicate that liver-specific miR-122 expression was significantly reduced in sorafenib-resistant cells. Overexpression of miR-122 made drug-tolerant cells sensitive to sorafenib and induced apoptosis. Insulin-like growth factor 1 receptor (IGF-1R) was validated as a target of miR-122 and was repressed by this miRNA. miR-122-induced apoptosis was repressed by the IGF-1R activator IGFI or IGFII. Conversely, the IGF-1R inhibitor PPP or NVP-AEW541 in combination with sorafenib significantly induced cell apoptosis and disrupted tolerance to drugs in vitro. These results indicated that activation of IGF-1R by ectopic down-regulation of miR-122 counteracted the effects of sorafenib-induced apoptosis, thus conferring sorafenib resistance. Further study revealed that activation of IGF-1R by miR-122 down-regulation contributed to activation of RAS/RAF/ERK signaling, which was associated with drug resistance. Our data imply that an intimate correlation between miR-122 and IGF-1R abnormal expression is a critical determinant of sorafenib tolerance. (C) 2015 Elsevier Ireland Ltd. All rights reserved.