Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9076-E9085. doi: 10.1073/pnas.1712018114. Epub 2017 Oct 9.


High-risk human papillomaviruses (HPVs) infect epithelial cells and are causally associated with cervical cancer, but HPV infection is not sufficient for carcinogenesis. Previously, we reported that estrogen signaling in the stromal tumor microenvironment is associated with cervical cancer maintenance and progression. We have now determined how HPV oncogenes and estrogen treatment affect genome-wide host gene expression in laser-captured regions of the cervical epithelium and stroma of untreated or estrogen-treated nontransgenic and HPV-transgenic mice. HPV oncogene expression in the cervical epithelium elicited significant gene-expression changes in the proximal stromal compartment, and estrogen treatment uniquely affected gene expression in the cervical microenvironment of HPV-transgenic mice compared with nontransgenic mice. Several potential estrogen-induced paracrine-acting factors were identified in the expression profile of the cervical tumor microenvironment. The microenvironment of estrogen-treated HPV-transgenic mice was significantly enriched for chemokine/cytokine activity and inflammatory and immune functions associated with carcinogenesis. This inflammatory signature included several proangiogenic CXCR2 receptor ligands. A subset of the same CXCR2 ligands was likewise increased in cocultures of early-passage cells from human cervical samples, with levels highest in cocultures of cervical fibroblasts and cancer-derived epithelial cells. Our studies demonstrate that high-risk HPV oncogenes profoundly reprogram the tumor microenvironment independently of and synergistically with estrogen. These observations illuminate important means by which HPVs can cause cancer through alterations in the tumor microenvironment.

Keywords: cervical cancer; estrogen; human papillomavirus; paracrine signaling; stroma.

Publication types

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

MeSH terms

  • Animals
  • Chemokines / genetics
  • Chemokines / metabolism
  • Coculture Techniques
  • Cytokines / genetics
  • Cytokines / metabolism
  • Estrogens / metabolism*
  • Estrogens / pharmacology
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Host-Pathogen Interactions / genetics
  • Humans
  • Mice, Transgenic
  • Oncogene Proteins, Viral / genetics*
  • Oncogene Proteins, Viral / metabolism
  • Papillomavirus E7 Proteins / genetics*
  • Papillomavirus E7 Proteins / metabolism
  • Papillomavirus Infections / metabolism
  • Papillomavirus Infections / pathology*
  • Papillomavirus Infections / virology
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology*


  • Chemokines
  • Cytokines
  • E6 protein, Human papillomavirus type 16
  • Estrogens
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Repressor Proteins
  • oncogene protein E7, Human papillomavirus type 16