Human papilloma virus (HPV) E7-mediated attenuation of retinoblastoma (Rb) induces hPygopus2 expression via Elf-1 in cervical cancer

Mol Cancer Res. 2013 Jan;11(1):19-30. doi: 10.1158/1541-7786.MCR-12-0510. Epub 2013 Jan 2.

Abstract

The human papillomavirus (HPV) is the etiologic agent of cervical cancer. In this study, we provide evidence for the human Pygopus (hPygo)2 gene as a cellular biomarker for HPV-related disease. In a tumor microarray of cervical cancer progression, hPygo2 levels were greater in high-grade lesions and squamous cell carcinomas than in normal epithelia. Similarly, hPygo2 mRNA and protein levels were greater in HPV-positive cervical cancer cells relative to uninfected primary cells. RNA interference (RNAi)-mediated depletion of HPV-E7 increased whereas E74-like factor (Elf)-1 RNAi decreased association of Retinoblastoma (Rb) tumor suppressor with the hPygo2 promoter in cervical cancer cell lines. Transfection of dominant-active Rb inhibited Elf-1-dependent activation of hPygo2, whereas Elf-1 itself increased hPygo2 expression. Chromatin immunoprecipitation assays showed that Rb repressed hPygo2 by inhibiting Elf-1 at the Ets-binding site in the hPygo2 promoter. These results suggested that abrogation of Rb by E7 resulted in derepression of Elf-1, which in turn stimulated expression of hPygo2. Thus, initiation of hPygo2 expression by Elf-1 was required for proliferation of cervical cancer cells and its expression therefore may act as a surrogate marker for dysplasia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Transformation, Viral / genetics
  • Ephrin-A2 / genetics
  • Ephrin-A2 / metabolism*
  • Female
  • Human papillomavirus 16 / genetics
  • Human papillomavirus 16 / metabolism
  • Human papillomavirus 18 / genetics
  • Human papillomavirus 18 / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / biosynthesis*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / metabolism*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / metabolism*
  • Papillomavirus Infections / pathology
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism*
  • Transfection
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology*

Substances

  • Ephrin-A2
  • Intracellular Signaling Peptides and Proteins
  • PYGO2 protein, human
  • Papillomavirus E7 Proteins
  • Retinoblastoma Protein