Cancer susceptibility of beta HPV49 E6 and E7 transgenic mice to 4-nitroquinoline 1-oxide treatment correlates with mutational signatures of tobacco exposure

Virology. 2019 Dec:538:53-60. doi: 10.1016/j.virol.2019.09.010. Epub 2019 Sep 24.

Abstract

We have previously showed that a transgenic (Tg) mouse model with cytokeratin 14 promoter (K14)-driven expression of E6 and E7 from beta-3 HPV49 in the basal layer of the epidermis and of the mucosal epithelia of the digestive tract (K14 HPV49 E6/E7 Tg mice) are highly susceptible to upper digestive tract carcinogenesis upon exposure to 4-nitroquinoline 1-oxide (4NQO). Using whole-exome sequencing, we show that in K14 HPV49 E6/E7 Tg mice, development of 4NQO-induced cancers tightly correlates with the accumulation of somatic mutations in cancer-related genes. The mutational signature in 4NQO-treated mice was similar to the signature observed in humans exposed to tobacco smoking and tobacco chewing. Similar results were obtained with K14 Tg animals expressing mucosal high-risk HPV16 E6 and E7 oncogenes. Thus, beta-3 HPV49 share some functional similarities with HPV16 in Tg animals.

Keywords: 4-Nitroquinoline 1-oxide; Beta HPV types; Mutational signatures of tobacco exposure; Upper-digestive tract cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Nitroquinoline-1-oxide / toxicity*
  • Animals
  • Betapapillomavirus / genetics
  • Betapapillomavirus / metabolism*
  • Disease Susceptibility
  • Female
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation / drug effects
  • Neoplasms / etiology
  • Neoplasms / genetics*
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism*
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / metabolism*
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / virology*
  • Tobacco Products

Substances

  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • 4-Nitroquinoline-1-oxide