NFκB-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation.
NFκB-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation.
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DOI：
10.1016/j.cellsig.2013.08.005
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发表时间：
2013-12
影响因子：
4.8
通讯作者：
Choudhury GG
中科院分区：
文献类型：
--
作者：
Bera A;Ghosh-Choudhury N;Dey N;Das F;Kasinath BS;Abboud HE;Choudhury GG
在包括肾细胞癌在内的许多肿瘤中，microRNAs调控转录后的格局。我们最近发现miR-21在肾肿瘤中的表达显著增加，并且这种miRNA有助于培养的肾癌细胞的增殖。然而，miR-21调控肾癌细胞增殖的机制尚不清楚。对原生性核因子κB活性的依赖是包括肾癌在内的许多癌症的特征。在肾癌细胞中使用miR-21海绵阻断miR-21的内源性功能，我们发现抑制了NFκB、IKKβ和IκB的p65亚基的磷酸化，从而导致了NFκB转录活性的减弱。肿瘤抑制基因PTEN的微妙减少与多种恶性肿瘤有关。我们先前已经证明miR-21靶向于肾癌细胞中的PTEN。SiRNAs抑制PTEN可恢复miR-21海绵诱导的p65、IKKβ、IκB和NFκB转录活性的磷酸化抑制，并逆转miR-21海绵诱导的Akt的磷酸化。组成性活性AKT的表达可保护p65/IKKβ/IκB的磷酸化和转录活性的降低。此外，IKKβ和p65是miR-21诱导肾癌细胞增殖所必需的。有趣的是，miR-21通过依赖于核因子κB的转录来控制细胞周期蛋白D1的表达。最后，我们证明miR-21调控肾癌细胞的增殖是由细胞周期蛋白D1和CDK4介导的。综上所述，我们的结果建立了一个涉及pTen/akt/ikkβ和NFκB依赖的细胞周期蛋白D1表达的磷酸酶-激酶对的分子顺序，通过上调miR-21水平促进肾癌细胞的增殖。
MicroRNAs regulate post-transcriptomic landscape in many tumors including renal cell carcinoma. We have recently shown significantly increased expression of miR-21 in renal tumors and that this miRNA contributes to the proliferation of renal cancer cells in culture. However, the mechanism by which miR-21 regulates renal cancer cells proliferation is poorly understood. Addiction to constitutive NFκB activity is hallmark of many cancers including renal cancer. Using miR-21 Sponge in renal cancer cells to block endogenous function of miR-21, we show inhibition of phosphorylation of p65 subunit of NFκB, IKKβ and IκB, which results in attenuation of NFκB transcriptional activity. Subtle reduction in the tumor suppressor PTEN has been linked to various malignancies. We showed previously that miR-21 targeted PTEN in renal cancer cells. Inhibition of PTEN by siRNAs restored miR-21 Sponge-induced suppression of phosphorylation of p65, IKKβ, IκB and NFκB transcriptional activity along with reversal of miR-21 Sponge-reduced phosphorylation of Akt. Expression of constitutively active Akt protected against miR-21 Sponge- and PTEN-mediated decrease in p65/IKKβ/IκB phosphorylation and NFκB transcriptional activity. Furthermore, IKKβ and p65 were required for miR-21-induced renal cancer cell proliferation. Interestingly, miR-21 controlled the expression of cyclin D1 through NFκB-dependent transcription. Finally, we demonstrate that miR-21-regulated renal cancer cell proliferation is mediated by cyclin D1 and CDK4. Together, our results establish a molecular order of a phosphatase-kinase couple involving PTEN/Akt/IKKβ and NFκB-dependent cyclin D1 expression for renal carcinoma cell proliferation by increased miR-21 levels.
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影响因子：
8.8
作者：
Aaltomaa, S;Lipponen, P;Ala-Opas, M;Eskelinen, M;Syrjänen, K;Kosma, VM
通讯作者：
Kosma, VM
影响因子：
6.2
作者：
Abou Youssif, Tamer;Fahmy, Mona Alam;Sircar, Kanishka
通讯作者：
Sircar, Kanishka
影响因子：
7.3
作者：
He L
通讯作者：
He L
影响因子：
11.2
作者：
Carracedo A;Alimonti A;Pandolfi PP
通讯作者：
Pandolfi PP
影响因子：
2.1
作者：
Juan, David;Alexe, Gabriela;Liou, Louis S.
通讯作者：
Liou, Louis S.