Activation of miR-9 by human papillomavirus in cervical cancer

Oncotarget. 2014 Nov 30;5(22):11620-30. doi: 10.18632/oncotarget.2599.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Movement
  • Down-Regulation
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Viral
  • Humans
  • MicroRNAs / metabolism*
  • Middle Aged
  • Oncogene Proteins, Viral / metabolism
  • Papillomaviridae
  • Papillomavirus Infections / virology*
  • Prognosis
  • Repressor Proteins / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / metabolism
  • Uterine Cervical Neoplasms / virology*

Substances

  • E6 protein, Human papillomavirus type 16
  • MIRN92 microRNA, human
  • MicroRNAs
  • Oncogene Proteins, Viral
  • Repressor Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • oncogene protein E7, Human papillomavirus type 6