Strong inverse correlation between microRNA-125b and human papillomavirus DNA in productive infection

Diagn Mol Pathol. 2010 Sep;19(3):135-43. doi: 10.1097/PDM.0b013e3181c4daaa.

Abstract

Infection by the human papillomavirus (HPV) is a cause of cervical intraepithelial neoplasia (CIN) and cancer. microRNA (miRNA) in situ analysis of the transformation zone epithelia, the site of initial cervical HPV infection, showed that miRNAs let-7c, -99a, 26a, and 125b were the most abundantly expressed. In situ testing of CIN 1 showed a dramatic reduction in miR-125b expression in the koilocytes, the cytologic marker of productive HPV infection. A marked reduction in miR-125b was likewise observed in the HPV-infected cells of the condyloma acuminatum, verruca vulgaris, and epidermodysplasia verruciformis. Reverse transcriptase in situ polymerase chain reaction (PCR) showed that the pre-miRNA 125b was present in the koilocyte, suggesting direct inactivation of the mature miRNA. HEK cells transfected with only the antimiR-125b showed perinuclear halos equivalent to HPV-infected koilocytes. NIH 3T3 cells transfected with the HPV 16 full-length genome and mimetic miR-125b showed a marked reduction in viral DNA and protein synthesis by quantitative PCR and in situ-based analyses, respectively (P=0.002). Alternatively, cotransfection with anti-miR-125b and HPV 16 markedly increased HPV DNA (P=0.002). Sequence analyses showed strong homology between L2 of different HPV genotypes and miR-125b. Transfection with HPV 16 L2 resulted in a marked reduction in miR-125b levels in the NIH 3T3 cells. HPV L2-induced inactivation of miR-125b is associated with the classic cytologic changes of the koilocyte, and the exogenous application of mimetic miR-125b markedly inhibits HPV DNA synthesis.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cervical Intraepithelial Neoplasia / pathology
  • Cervical Intraepithelial Neoplasia / virology
  • Cervix Uteri / cytology
  • Cervix Uteri / pathology
  • Condylomata Acuminata / pathology
  • Condylomata Acuminata / virology
  • DNA, Viral / analysis*
  • DNA, Viral / genetics
  • Epidermodysplasia Verruciformis / pathology
  • Epidermodysplasia Verruciformis / virology
  • Epithelial Cells / pathology
  • Female
  • Humans
  • Mice
  • MicroRNAs / analysis*
  • MicroRNAs / genetics
  • Papillomaviridae / genetics*
  • Papillomaviridae / isolation & purification
  • Papillomavirus Infections / pathology*
  • Papillomavirus Infections / virology
  • Warts / pathology
  • Warts / virology

Substances

  • DNA, Viral
  • MIRN125 microRNA, human
  • MicroRNAs