miR-1182 attenuates gastric cancer proliferation and metastasis by targeting the open reading frame of hTERT
miR-1182 attenuates gastric cancer proliferation and metastasis by targeting the open reading frame of hTERT
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miR-1182通过靶向hTERT开放阅读框来减弱胃癌增殖和转移
DOI：
10.1016/j.canlet.2015.01.044
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发表时间：
2015-05-01
期刊：
影响因子：
9.7
通讯作者：
Yang, Shi-Ming
中科院分区：
文献类型：
--
作者：
Zhang, Dan;Xiao, Yu-Feng;Yang, Shi-Ming
在人类中，端粒酶逆转录酶（hTERT）决定端粒酶的活性。hTERT是一个理想的抗癌靶点，因为它在癌细胞中普遍表达，并在肿瘤发生中起着至关重要的作用。在这项研究中，我们报告了miR-1182介导的hTERT转录后调控。miR-1182在不同胃癌细胞中的过表达降低了hTERT蛋白水平。生物信息学和双荧光素酶分析表明，miR-1182通过与其开放阅读框（ORF）结合来调节hTERT，该miRNA识别hTERT mRNA的2695 - 2719核苷酸区域中的元件。miR-1182可抑制pIRES 2-hTERT在U2 OS细胞中的过度表达，而miR-1182靶位点发生同步突变的pIRES 2-hTERT-MT对miR-1182无反应。进一步研究发现miR-1182通过靶向hTERT的ORF 1抑制胃癌细胞的增殖和迁移。我们还发现miR-1182在体内可抑制SGC-7901细胞的增殖和转移能力。此外，我们发现42例胃癌患者组织中miR-1182和hTERT蛋白水平之间存在统计学显著负相关。这些数据表明，miR-1182抑制TERT，因此它可能是治疗胃癌的有效靶点。(C)2015爱思唯尔爱尔兰有限公司版权所有。
In humans, telomerase reverse transcriptase (hTERT) determines the activity of telomerase. hTERT is an ideal anticancer target because it is universally expressed in cancer cells and plays a crucial role in carcinogenesis. In this study, we report the miR-1182-mediated post-transcriptional regulation of hTERT. Over-expression of miR-1182 in different gastric cancer cells decreased hTERT protein levels. Bioinformation and dual-luciferase assays revealed that miR-1182 modulated hTERT by binding to its open reading frame (ORF), and this miRNA recognizes elements in the nucleotide region between 2695 and 2719 of hTERT mRNA. Over-expression of hTERT by transfecting pIRES2-hTERT into U2OS cells was abolished by miR-1182, while pIRES2-hTERT-MT, in which miR-1182 target site was synonymously mutated, failed to respond to miR-1182. Further investigation revealed that miR-1182 inhibited gastric cancer proliferation and migration by targeting the ORF1 of hTERT. We also found that miR-1182 could attenuate the proliferative and metastatic potential of SGC-7901 cell in vivo. Moreover, we found a statistically significant inverse correlation between miR-1182 and hTERT protein levels in tissues from 42 gastric cancer patients. These data indicate that miR-1182 suppresses TERT, and thus it could be an effective target for the treatment of gastric cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.