MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway.
MiR-21 mediates sorafenib resistance of hepatocellular carcinoma cells by inhibiting autophagy via the PTEN/Akt pathway.
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MiR-21 通过 PTEN/Akt 通路抑制自噬来介导肝细胞癌细胞索拉非尼耐药。
DOI：
10.18632/oncotarget.4814
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发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Sun X
中科院分区：
文献类型：
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作者：
He C;Dong X;Zhai B;Jiang X;Dong D;Li B;Jiang H;Xu S;Sun X
索拉非尼耐药仍然是肝细胞癌（HCC）有效治疗的主要障碍。近期研究表明，激活的蛋白激酶B（Akt）会导致对索拉非尼产生获得性耐药，且微小RNA - 21（miR - 21）会失调磷酸酶及张力蛋白同源物（PTEN），而PTEN可抑制Akt的激活。研究显示，索拉非尼耐药的肝癌细胞对索拉非尼诱导的生长抑制和细胞凋亡具有抗性。在索拉非尼耐药细胞中，Akt及其下游因子高度激活和/或上调。抑制自噬会降低索拉非尼耐药细胞对索拉非尼的敏感性，而诱导自噬则产生相反效果。对微小RNA的差异筛选表明，索拉非尼耐药的肝癌细胞中miR - 21水平较高。肝癌细胞暴露于索拉非尼会导致miR - 21表达增加、PTEN表达减少以及Akt的相继激活。在肝癌细胞中转染miR - 21模拟物可通过抑制自噬恢复对索拉非尼的耐药性。抗miR - 21寡核苷酸则通过促进自噬使索拉非尼耐药细胞重新敏感。抑制miR - 21可增强索拉非尼在体内治疗索拉非尼耐药性肝癌肿瘤的疗效。我们得出结论，miR - 21通过Akt/PTEN通路抑制自噬，从而参与索拉非尼的获得性耐药过程。miR - 21有望成为克服肝癌治疗中索拉非尼耐药性的治疗靶点。
Sorafenib resistance remains a major obstacle for the effective treatments of hepatocellular carcinoma (HCC). Recent studies indicate that activated Akt contributes to the acquired resistance to sorafenib, and miR-21 dysregulates phosphatase and tensin homolog (PTEN), which inhibits Akt activation. Sorafenib-resistant HCC cells were shown to be refractory to sorafenib-induced growth inhibition and apoptosis. Akt and its downstream factors were highly activated and/or upregulated in sorafenib-resistant cells. Inhibition of autophagy decreased the sensitivity of sorafenib-resistant cells to sorafenib, while its induction had the opposite effect. Differential screening of miRNAs showed higher levels of miR-21 in sorafenib-resistant HCC cells. Exposure of HCC cells to sorafenib led to an increase in miR-21 expression, a decrease in PTEN expression and sequential Akt activation. Transfection of miR-21 mimics in HCC cells restored sorafenib resistance by inhibiting autophagy. Anti-miR-21 oligonucleotides re-sensitized sorafenib-resistant cells by promoting autophagy. Inhibition of miR-21 enhances the efficacy of sorafenib in treating sorafenib-resistant HCC tumors in vivo. We conclude that miR-21 participates in the acquired resistance of sorafenib by suppresing autophagy through the Akt/PTEN pathway. MiR-21 could serve as a therapeutic target for overcoming sorafenib resistance in the treatment of HCC.