Activation of miR-9 by human papillomavirus in cervical cancer.
Activation of miR-9 by human papillomavirus in cervical cancer.
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DOI：
10.18632/oncotarget.2599
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发表时间：
2014-11-30
期刊：
影响因子：
--
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Liu W;Gao G;Hu X;Wang Y;Schwarz JK;Chen JJ;Grigsby PW;Wang X
宫颈癌是世界范围内女性第三大常见癌症，每年导致约30万人死亡。大多数宫颈癌是由人乳头瘤病毒（HPV）感染引起的。然而，HPV癌基因的持续转录活性，这表明HPV在宫颈癌的维持和进展中的积极作用，尚未得到很好的表征。使用我们最近开发的用于HPV E6/E7转录物综合分析的检测方法，我们检测了分析中101个宫颈肿瘤中87个的10种高危HPV株的转录活性。与HPV阴性患者相比，这些HPV阳性患者的生存结局明显更好，表明HPV转录活性是宫颈癌的有利预后标志物。此外，我们还确定了与肿瘤HPV状态相关的microRNA（miRNA）表达变化。我们的分析和功能分析确定miR-9是HPV E6以p53非依赖性方式激活最多的miRNA。进一步的靶点验证和功能研究表明，HPV诱导的miR-9激活通过下调参与细胞迁移的多个基因靶点导致细胞运动性显著增加。因此，我们的工作有助于了解宫颈癌和其他HPV诱导的癌症的分子机制，并确定潜在的治疗靶点。
Cervical cancer is the third most common cancer in women worldwide, leading to about 300,000 deaths each year. Most cervical cancers are caused by human papillomavirus (HPV) infection. However, persistent transcriptional activity of HPV oncogenes, which indicates active roles of HPV in cervical cancer maintenance and progression, has not been well characterized. Using our recently developed assays for comprehensive profiling of HPV E6/E7 transcripts, we have detected transcriptional activities of 10 high-risk HPV strains from 87 of the 101 cervical tumors included in the analysis. These HPV-positive patients had significantly better survival outcome compared with HPV-negative patients, indicating HPV transcriptional activity as a favorable prognostic marker for cervical cancer. Furthermore, we have determined microRNA (miRNA) expression changes that were correlated with tumor HPV status. Our profiling and functional analyses identified miR-9 as the most activated miRNA by HPV E6 in a p53-independent manner. Further target validation and functional studies showed that HPV-induced miR-9 activation led to significantly increased cell motility by downregulating multiple gene targets involved in cell migration. Thus, our work helps to understand the molecular mechanisms as well as identify potential therapeutic targets for cervical cancer and other HPV-induced cancers.
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