miR-221 regulates CD44 in hepatocellular carcinoma through the PI3K-AKT-mTOR pathway.
miR-221 regulates CD44 in hepatocellular carcinoma through the PI3K-AKT-mTOR pathway.
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miR-221通过PI3K-AKT-MTOR途径调节肝细胞癌中的CD44。
DOI：
10.1016/j.bbrc.2017.04.121
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发表时间：
2017-06-03
影响因子：
3.1
通讯作者：
Schmittgen TD
中科院分区：
文献类型：
--
作者：
Kim J;Jiang J;Badawi M;Schmittgen TD
CD44和miR-221在肝细胞癌（HCC）细胞系和肿瘤中上调，但两者之间的联系尚未确定。由于miR-221在HCC细胞中的表达与CD44直接相关，我们假设miR-221可能直接或间接调节CD44的表达。在Sk-Hep-1或SNU-449细胞系中，用反义抑制miR-221可降低CD44蛋白表达，而miR-221模拟物可增加CD44蛋白水平。miR-221反义不改变Sk-Hep-1或SNU-449细胞中的CD44 mRNA水平，提示CD44蛋白的调控发生在转录后。为了发现可能参与miR-221调控CD44的miRNA，我们在抗miR-221处理的SNU-449细胞中进行了miRNA分析。随着miR-221的抑制，几种miRNA增加，包括miR-708-5p，一种靶向CD44的miRNA。由于miR-221靶向PI3K-AKT-mTOR途径的几种调节因子，并且该途径与CD44之间的联系先前已在前列腺癌中得到证实，因此我们认为miR-221可能通过该途径调节CD44。miR-221的抑制降低了PI3K-AKT-mTOR途径的下游效应物p-4EBP1。同样，用ATP竞争性mTOR抑制剂PP242抑制PI3K-AKT-mTOR通路可降低SNU-423和SNU-449细胞中的CD44蛋白，但不改变CD44 mRNA水平。
CD44 and miR-221 are upregulated in hepatocellular carcinoma (HCC) cell lines and tumors, however a connection between the two has not been identified. As the expression of miR-221 directly correlated with CD44 in HCC cells, we hypothesized that miR-221 may directly or indirectly regulate CD44 expression. Inhibition of miR-221 with antisense in Sk-Hep-1 or SNU-449 cell lines reduced CD44 protein expression while miR-221 mimic increased CD44 protein levels. miR-221 antisense did not alter the CD44 mRNA levels in Sk-Hep-1 or SNU-449 cells suggesting that regulation of CD44 protein occurs post transcriptionally. To discover miRNAs that may be involved in the miR-221 regulation of CD44, we performed miRNA profiling in SNU-449 cells treated with anti-miR-221. Several miRNAs were increased with miR-221 inhibition including miR-708-5p, a miRNA that targets CD44. As miR-221 targets several regulators of the PI3K-AKT-mTOR pathway and a link between this pathway and CD44 has been previously shown in prostate cancer, we considered miR-221 regulation of CD44 may be through this pathway. Inhibition of miR-221 reduced p-4EBP1, a downstream effector of the PI3K-AKT-mTOR pathway. Likewise, inhibiting the PI3K-AKT-mTOR pathway with the ATP- competitive mTOR inhibitor PP242 reduced CD44 protein in SNU-423 and SNU-449 cells without altering CD44 mRNA levels.
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影响因子：
11.2
作者：
Gramantieri, Laura;Ferracin, Manuela;Negrini, Massimo
通讯作者：
Negrini, Massimo
影响因子：
50.3
作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
通讯作者：
Saya, Hideyuki
影响因子：
3
作者：
Serova, Maria;de Gramont, Armand;Raymond, Eric
通讯作者：
Raymond, Eric
影响因子：
64.8
作者：
Hsieh, Andrew C.;Liu, Yi;Edlind, Merritt P.;Ingolia, Nicholas T.;Janes, Matthew R.;Sher, Annie;Shi, Evan Y.;Stumpf, Craig R.;Christensen, Carly;Bonham, Michael J.;Wang, Shunyou;Ren, Pingda;Martin, Michael;Jessen, Katti;Feldman, Morris E.;Weissman, Jonathan S.;Shokat, Kevan M.;Rommel, Christian;Ruggero, Davide
通讯作者：
Ruggero, Davide
影响因子：
50.3
作者：
Garofalo M;Di Leva G;Romano G;Nuovo G;Suh SS;Ngankeu A;Taccioli C;Pichiorri F;Alder H;Secchiero P;Gasparini P;Gonelli A;Costinean S;Acunzo M;Condorelli G;Croce CM
通讯作者：
Croce CM