MiR-199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1.
MiR-199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1.
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MiR-199a-3p通过抑制mTOR信号通路和MDR1表达增强胆管癌细胞对顺铂的敏感性
DOI：
10.18632/oncotarget.16834
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发表时间：
2017-05-16
期刊：
影响因子：
--
通讯作者：
Chen W
中科院分区：
文献类型：
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作者：
Li Q;Xia X;Ji J;Ma J;Tao L;Mo L;Chen W
一些研究报道了不同人类恶性肿瘤中减少的miRNA-199 a-3 p（miR-199 a-3 p），然而，关于胆管癌细胞中的miR-199 a-3 p知之甚少。在这项研究中，我们证明了miR-199 a-3 p在胆管癌细胞系中调节顺铂敏感性的重要作用和机制。使用CCK-8细胞计数法，我们发现miR-199 a-3 p的表达与胆管癌细胞系中顺铂敏感性正相关。miR-199 a-3 p过表达可降低顺铂作用下胆管癌细胞的增殖率，增加细胞凋亡，而miR-199 a-3 p抑制则相反。进一步的研究表明，mTOR是miR-199 a-3 p的靶基因，miR-199 a-3 p模拟物可以抑制mTOR的表达，从而降低其下游蛋白4 EBP 1和p70 s6 k的磷酸化水平。挽救实验证明miR-199 a-3 p可通过调节mTOR表达增加胆管癌细胞系对顺铂的敏感性。此外，我们还发现miR-199 a-3 p过表达可通过减少MDR 1的合成和增加MDR 1的降解来降低顺铂诱导的MDR 1表达，从而增强顺铂对胆管癌的疗效。结论：miR-199 a-3 p可通过抑制mTOR信号通路的活性，降低MDR 1的表达，提高胆管癌细胞对顺铂的敏感性。
Several studies have reported reduced miRNA-199a-3p (miR-199a-3p) in different human malignancies, however, little is known about miR-199a-3p in cholangiocarcinoma cells. In this study, we demonstrate the essential role and mechanism of miR-199a-3p in regulating cisplatin sensitivity in cholangiocarcinoma cell lines. Using a CCK-8 cell counting assay we found that expression of miR-199a-3p was positively correlated with cisplatin sensitivity in cholangiocarcinoma cell lines. MiR-199a-3p overexpression could decrease the proliferation rate and increase apoptosis of cholangiocarcinoma cells in the presence of cisplatin, while miR-199a-3p inhibition had the opposite effect. Further study demonstrated that mTOR was the target gene of miR-199a-3p, and that miR-199a-3p mimics could inhibit expression of mTOR, which consequently reduced the phosphorylation of its downstream proteins 4EBP1 and p70s6k. Rescue experiments proved that miR-199a-3p could increase the cisplatin sensitivity of cholangiocarcinoma cell lines by regulating mTOR expression. Moreover, we also found that miR-199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma. In conclusion, miR-199a-3p could increase cisplatin sensitivity of cholangiocarcinoma cell lines by inhibiting the activity of the mTOR signaling pathway and decreasing the expression of MDR1.