Activation of miR-9 by human papillomavirus in cervical cancer
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Weijun Liu1,*, Ge Gao1,*, Xiaoxia Hu6,1,*, Yuhui Wang7,1, Julie K. Schwarz1,3,4, Jason J. Chen5, Perry W. Grigsby1,2,4 and Xiaowei Wang1,4
1 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri
2 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri
3 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri
4 Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
5 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
6 People’s Hospital of Guangxi Province, Nanning, China.
7 Pre-clinic and Forensic Medical School, Sichuan University, Chengdu, China
* These authors contributed equally to this work
Xiaowei Wang, email:
Keywords: microRNA; miR-9; human papillomavirus; cervical cancer; expression profiling
Received: August 15, 2014 Accepted: October 18, 2014 Published: October 18, 2014
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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