Interaction between Cigarette Smoke and Human Papillomavirus 16 E6/E7 Oncoproteins to Induce SOD2 Expression and DNA Damage in Head and Neck Cancer

Abstract

Even though epidemiological studies suggest that tobacco smoking and high-risk human papillomavirus (HR-HPV) infection are mutually exclusive risk factors for developing head and neck cancer (HNC), a portion of subjects who develop this heterogeneous group of cancers are both HPV-positive and smokers. Both carcinogenic factors are associated with increased oxidative stress (OS) and DNA damage. It has been suggested that superoxide dismutase 2 (SOD2) can be independently regulated by cigarette smoke and HPV, increasing adaptation to OS and tumor progression. In this study, we analyzed SOD2 levels and DNA damage in oral cells ectopically expressing HPV16 E6/E7 oncoproteins and exposed to cigarette smoke condensate (CSC). Additionally, we analyzed SOD2 transcripts in The Cancer Genome Atlas (TCGA) Head and Neck Cancer Database. We found that oral cells expressing HPV16 E6/E7 oncoproteins exposed to CSC synergistically increased SOD2 levels and DNA damage. Additionally, the SOD2 regulation by E6, occurs in an Akt1 and ATM-independent manner. This study suggests that HPV and cigarette smoke interaction in HNC promotes SOD2 alterations, leading to increased DNA damage and, in turn, contributing to development of a different clinical entity.

Exploring the Link between Head and Neck Cancer and the Elevated Risk of Acute Myocardial Infarction: A National Population-Based Cohort Study

“…HNC and ischemic cardiovascular disease share common risk factors, including tobacco use, alcohol consumption, and, for some types of HNC, human papillomavirus infection. These shared risk factors can independently contribute to the development of both conditions [25][26][27]. However, to date, there have been no detailed investigations of the risk of ischemic events associated with HNC.…”

Contributions of viral oncogenes of HPV-18 and hypoxia to oxidative stress and genetic damage in human keratinocytes

“…HPV oncogenes induce both oxidative stress and DNA damage 20 , 21 in different tumor types frequently associated with HPV infection, such as head and neck cancer 34 . Also, expression of HPV oncogenes E6 and E7 in normal cells results in DNA damage and genomic instability 21 , one of the hallmarks of HPV-induced carcinogenesis.…”

Gender Difference in DNA Damage Induced by the Environmental Carcinogen Dibenzo[def,p]chrysene Individually and in Combination with Mouse Papillomavirus Infection in the Mouse Oral Cavity

“…The International Agency for Research on Cancer classified HPV16 as oncogenic to a number of cancer sites . In contrast to cervical cancer, cofactors, such as tobacco smoking, for HPV-associated OPSCC are not fully defined . Our knowledge of the carcinogenesis process from HPV infection to the OPSCC is limited and mostly extrapolated from cervical cancer models.…”

“…18 In contrast to cervical cancer, 19 cofactors, such as tobacco smoking, for HPV-associated OPSCC are not fully defined. 20 Our knowledge of the carcinogenesis process from HPV infection to the OPSCC is limited and mostly extrapolated from cervical cancer models. Using our established mouse papillomavirus (MmuPV1) infection model, no tumor was observed in the oral cavity of mice infected with the virus alone during the duration of the bioassay but a very low tumor incidence was observed in mice treated with DB[ a,l ]P at the dose used in that study.…”