The environmental pollutant and tobacco smoke constituent dibenzo[def,p]chrysene is a co-factor for malignant progression of mouse oral papillomavirus infections

HPV infections in the oral cavity that progress to cancer are on the increase in the USA. Model systems to study co-factors for progression of these infections are lacking as HPVs are species-restricted and cannot grow in preclinical animal models. We have recently developed a mouse papillomavirus (MmuPV1) oral mucosal infection model that provides opportunities to test, for the first time, the hypothesis that tobacco carcinogens are co-factors that can impact the progression of oral papillomas to squamous cell carcinoma (SCC). Four cohorts of mice per sex were included: (1) infected with MmuPV1 and treated orally with DMSO-saline; (2) infected with MmuPV1 and treated orally with the tobacco carcinogen, dibenzo[def,p]chrysene (DBP); (3) uninfected and treated orally with DMSO-saline, and (4) uninfected and treated orally with DBP. Oral swabs were collected monthly for subsequent assessment of viral load. Oral tissues were collected for in situ viral DNA/RNA detection, viral protein staining, and pathological assessment for hyperplasia, papillomas and SCC at study termination. We observed increased rates of SCC in oral tissue infected with MmuPV1 and treated with DBP when compared to mice treated with DBP or virus individually, each of which showed minimal disease. Virally-infected epithelium showed strong levels of viral DNA/RNA and viral protein E4/L1 staining. In contrast, areas of SCC showed reduced viral DNA staining indicative of lower viral copy per nucleus but strong RNA signals. Several host markers (p120 ctn, p53, S100A9) were also examined in the mouse oral tissues; of particular significance, p120 ctn discriminated normal un-infected epithelium from SCC or papilloma epithelium. In summary, we have confirmed that our infection model is an excellent platform to assess the impact of co-factors including tobacco carcinogens for oral PV cancerous progression. Our findings can assist in the design of novel prevention/treatment strategies for HPV positive vs. HPV negative disease.

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Work Title The environmental pollutant and tobacco smoke constituent dibenzo[def,p]chrysene is a co-factor for malignant progression of mouse oral papillomavirus infections
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Open Access
Creators
  1. Neil D. Christensen
  2. Kun-Ming Chen
  3. Jiafen Hu
  4. Douglas B. Stairs
  5. Yuan-Wan Sun
  6. Cesar Aliaga
  7. Karla K. Balogh
  8. Hannah Atkins
  9. Debra Shearer
  10. Jingwei Li
  11. Sarah A. Brendle
  12. Krishne Gowda
  13. Shantu Amin
  14. Vonn Walter
  15. Raphael Viscidi
  16. Karam El-Bayoumy
Keyword
  1. Human papillomavirus
  2. Mouse papillomavirus
  3. Tobacco carcinogens
  4. Oral cavity
  5. Squamous cell carcinoma
  6. p120 ctn
License In Copyright (Rights Reserved)
Work Type Article
Publisher
  1. Chemico-Biological Interactions
Publication Date December 17, 2021
Publisher Identifier (DOI)
  1. https://doi.org/10.1016/j.cbi.2020.109321
Deposited July 20, 2022

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Version 1
published

  • Created
  • Added CBI_DBP_2020_MmuPV1.pdf
  • Added Creator Neil D. Christensen
  • Added Creator Kun Ming Chen
  • Added Creator Jiafen Hu
  • Added Creator Douglas B. Stairs
  • Added Creator Yuan Wan Sun
  • Added Creator Cesar Aliaga
  • Added Creator Karla K. Balogh
  • Added Creator Hannah Atkins
  • Added Creator Debra Shearer
  • Added Creator Jingwei Li
  • Added Creator Sarah A. Brendle
  • Added Creator Krishne Gowda
  • Added Creator Shantu Amin
  • Added Creator Vonn Walter
  • Added Creator Raphael Viscidi
  • Added Creator Karam El-Bayoumy
  • Published
  • Updated Keyword, Publication Date Show Changes
    Keyword
    • Human papillomavirus, Mouse papillomavirus, Tobacco carcinogens, Oral cavity, Squamous cell carcinoma, p120 ctn
    Publication Date
    • 2021-01-05
    • 2021-12-17
  • Renamed Creator Kun-Ming Chen Show Changes
    • Kun Ming Chen
    • Kun-Ming Chen
  • Renamed Creator Yuan-Wan Sun Show Changes
    • Yuan Wan Sun
    • Yuan-Wan Sun