miR-424 coordinates multilayered regulation of cell cycle progression to promote esophageal squamous cell carcinoma cell proliferation
miR-424 coordinates multilayered regulation of cell cycle progression to promote esophageal squamous cell carcinoma cell proliferation
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miR-424协调细胞周期进程的多层调控促进食管鳞状细胞癌细胞增殖
DOI：
10.1016/j.ebiom.2018.10.043
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发表时间：
2018-11-01
期刊：
影响因子：
11.1
通讯作者：
Yang, Hong
中科院分区：
文献类型：
--
作者：
Wen, Jing;Hu, Yi;Yang, Hong
背景：细胞周期失调与食管鳞癌的进展有关。本研究旨在评价miR-424在细胞周期调控和ESCC增殖中的作用。方法：体外和体内研究miR-424对细胞增殖的影响。用染色质免疫沉淀法检测miR-424的转录活性，用miRNA核糖核蛋白复合体免疫沉淀法验证miR-424与靶点的结合。结果：miR-424表达上调，与ESCC患者的预后不良相关。在体内外，miR-424的抑制或过表达分别抑制或促进了ESCC细胞的增殖。MIR-424的表达受E2F1转录调控，并在G1/S转换过程中上调。MiR-424基因的表达下调或过表达分别抑制或促进食管癌细胞的G1/S和G2/M期细胞周期转换，其作用分别由两个新发现的miR-424靶点PrKCD和WEE1介导。因此，miR-424基因敲除导致p21(Cip1)蛋白表达上调，导致p21(Cip1)蛋白的稳定性增强，其机制是通过激活pKCD和下游的p38MAPK和JNK信号来阻断CDK2的激活和G1/S的转变，而WEE1的升高则维持CDC2的非激活状态以阻断G2/M的转变。然而，CircLARP4可以海绵结合miR-424与PRKCD，从而破坏miR-424对G1/S进程的调节。解释：miR-424协调了一种未知的、多层次的ESCC细胞周期调控，以促进ESCC的增殖，并可能作为一种新的预后标志物和有效的治疗靶点。(C)2018年作者。爱思唯尔出版公司(Elsevier B.V.)
Background: Dysregulation of the cell cycle has been implicated in esophageal squamous cell carcinoma (ESCC) progression. This study aimed to evaluate the role of miR-424 in cell cycle regulation and ESCC proliferation.Methods: The role of miR-424 in cell proliferation was evaluated in vitro and in vivo. Transcriptional activation of miR-424 was determined using chromatin immunopredpitation, and binding of miR-424 to targets was verified using miRNA ribonucleoprotein complex immunoprecipitation.Findings: miR-424 was upregulated and correlated with poor survival in ESCC patients. Repression or overexpression of miR-424 respectively decreased or increased ESCC cell proliferation in vitro and in vivo. miR-424 expression is transcriptionally regulated by E2F1 and increased during G1/S transition. Knockdown or overexpression of miR-424 respectively inhibited or promoted both G1/S and G2/M cell cycle transitions in ESCC cells, and these effects were mediated by two newly identified miR-424 targets, PRKCD and WEE1, respectively. Consequently, elevation of PRKCD by miR-424 knockdown led to enhanced stability of the p21(Cip1) protein via increased activation of PRKCD and downstream p38 MAPK and JNK signaling to block CDK2 activation and G1/S transition, while elevated WEE1, maintained CDC2 in an inactive state to block G2/M transition. However, circLARP4 could sponge the binding of miR-424 to PRKCD, thus compromising the regulation of G1/S progression by miR-424.Interpretation: miR-424 coordinates a previously unknown, multi layered regulation of ESCC cell cycle progression to promote ESCC proliferation, and may be used as a novel prognostic marker and an effective therapeutic target for ESCCs. (C) 2018 The Authors. Published by Elsevier B.V.