miR-17-5p/20a are important markers for gastric cancer and murine double minute 2 participates in their functional regulation
miR-17-5p/20a are important markers for gastric cancer and murine double minute 2 participates in their functional regulation
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miR-17-5p/20a是胃癌的重要标志物，小鼠双分钟2参与其功能调节
DOI：
10.1016/j.ejca.2012.12.017
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发表时间：
2013-05-01
影响因子：
8.4
通讯作者：
Xu, Wenrong
中科院分区：
文献类型：
--
作者：
Wang, Mei;Gu, Hongbing;Xu, Wenrong
目的：目的：探讨miR-17- 5 p/20 a在胃癌发生、发展中的作用及其机制。方法：采用实时定量PCR方法检测110例胃癌组织中miR-17- 5 p/20 a的表达情况。microRNAs（miRNAs）模拟物和抑制剂用于揭示其在胃癌中的功能。将拮抗剂应用于体内治疗胃癌细胞来源的异种移植物。结果：miR-17 - 5 p/20 a在胃癌组织中表达上调。过表达miR-17- 5 p/20 a可促进胃癌细胞周期进程，抑制细胞凋亡，而敲低miR-17- 5 p/20 a则可导致细胞周期阻滞，增加细胞凋亡。p21和肿瘤蛋白p53诱导的核蛋白1（TP 53 INP 1）被验证为miR-17- 5 p/20 a的靶点。在小鼠异种移植模型中，针对miR-17- 5 p/20 a的拮抗剂通过上调p21和TP 53 INP 1显著抑制胃癌生长。胃癌组织中miR-17- 5 p/20 a与TP 53 INP 1呈负相关。小鼠双分钟2（MDM 2）被发现参与miRNA的调节和功能。在miRNA模拟物转染的胃癌细胞系中靶向抑制MDM 2可消除miR-17- 5 p/20 a功能和对p21表达的抑制。结论：miR-17- 5 p/20 a通过转录后调节p21和TP 53 INP 1，促进胃癌细胞增殖，抑制细胞凋亡。它们有可能成为胃癌治疗的标志物。MDM 2参与了胃癌中miR-17- 5 p/20 a的功能和p21的抑制，并且可能是miR-17- 5 p/20 a致癌作用的新机制。(C)2012爱思唯尔有限公司保留所有权利。
Aim: To investigate the potential roles and mechanisms of miR-17-5p/20a in human gastric cancer development and progression.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine miR-17-5p/20a expression profiles in 110 gastric cancer tissues. microRNAs' (miRNAs) mimics and inhibitors were used to reveal their function in gastric cancer. Antagomirs were applied to treating gastric cancer cell derived xenograft in vivo. Western blot and luciferase assays were performed to uncover the targets and mechanisms of miR-17-5p/20a.Results: miR-17-5p/20a levels were upregulated in human gastric cancer tissues. Overexpression of miR-17-5p/20a promoted gastric cancer cell cycle progression and inhibited cell apoptosis, whereas knockdown of miR-17-5p/20a resulted in cell cycle arrest and increased apoptosis. p21 and tumour protein p53-induced nuclear protein 1 (TP53INP1) were validated as the targets of miR-17-5p/20a. Antagomirs against miR-17-5p/20a significantly inhibited gastric cancer growth via upregulation of p21 and TP53INP1 in a mouse xenograft model. The negative relationship between miR-17-5p/20a and TP53INP1 was observed in patient gastric cancer tissues. Murine double minute 2 (MDM2) was found to be involved in miRNA regulation and function. Targeted inhibition of MDM2 in a miRNA mimic-transfected gastric cancer cell line abolished miR-17-5p/20a function and inhibition of p21 expression. MDM2 restoration by pCMV-MDM2 rescued the functionality.Conclusions: Our findings indicate that miR-17-5p/20a promote gastric cancer cell proliferation and inhibit cell apoptosis via post-transcriptional modulation of p21 and TP53INP1. They may be promising therapeutic markers for gastric cancer. MDM2 contributes to miR-17-5p/20a function and inhibition of p21 in gastric cancer, and may be a novel mechanism underlying the oncogenic roles of miR-17-5p/20a. (C) 2012 Elsevier Ltd. All rights reserved.