Tobacco smoke activates human papillomavirus 16 p97 promoter and cooperates with high-risk E6/E7 for oxidative DNA damage in lung cells

PLoS One. 2015 Apr 1;10(4):e0123029. doi: 10.1371/journal.pone.0123029. eCollection 2015.


We have previously shown a functional interaction between human papillomavirus type 16 (HPV-16) E6 and E7 oncoproteins and cigarette smoke condensate (CSC) in lung cells suggesting cooperation during carcinogenesis. The molecular mechanisms of such interaction, however, remain to be elucidated. Here we first present evidence showing that cigarette smoke condensate (CSC) has the ability to activate the HPV-16 p97 promoter by acting on the long control region (LCR) in lung epithelial cells. Interestingly, we observed that CSC-induced p97 promoter activation occurs in a dose-dependent manner in both tumor A-549 (lung adenocarcinoma), H-2170 (bronchial carcinoma), SiHa or Hela (cervical carcinoma) cells but not in non-tumor BEAS-2B (bronchial) or NL-20 (alveolar) lung cells unless they ectopically expressed the HPV-16 E6 and E7 oncogenes. In addition, we also observed a significant increase of primary DNA damage in tumor and non-tumor CSC-treated lung cells expressing HPV-16 E6 and E7 oncogenes suggesting a cooperative effect in this process, even though the contribution of E7 was significantly higher. Taken together, our results strongly suggest that tobacco smoke is able to induce the activation of the HPV-16 p97 promoter in cooperation with HPV-16 E6 and E7 oncogenes that, in turn, sensitize lung cells to tobacco smoke-induced DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / pathology
  • Alveolar Epithelial Cells / virology
  • Cell Line, Tumor
  • DNA Damage
  • Gene Expression Regulation, Viral
  • Human papillomavirus 16 / genetics*
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / virology*
  • Oncogene Proteins, Viral / genetics*
  • Oncogene Proteins, Viral / metabolism
  • Oxidation-Reduction
  • Papillomavirus E7 Proteins / genetics*
  • Papillomavirus E7 Proteins / metabolism
  • Papillomavirus Infections / virology
  • Promoter Regions, Genetic
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Risk
  • Smoking / adverse effects*


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

Grant support

This study was funded by Fondo Nacional de Ciencia y Tecnología (Fondecyt) (1120248 to F.A., 11121339 to R.SR.) and Fondap 15130011 to A.H.C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.