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Oncotarget. 2016 Apr 12;7(15):19850-62. doi: 10.18632/oncotarget.7628.

Environmental exposure and HPV infection may act synergistically to induce lung tumorigenesis in nonsmokers.

Cheng YW1,2, Lin FC3,4, Chen CY3,4, Hsu NY1,2,5.

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Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan.
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan.


Most studies of lung tumorigenesis have focused on smokers rather than nonsmokers. In this study, we used human papillomavirus (HPV)-positive and HPV-negative lung cancer cells to test the hypothesis that HPV infection synergistically increases DNA damage induced by exposure to the carcinogen benzo[a]pyrene (B[a]P), and contributes to lung tumorigenesis in nonsmokers. DNA adduct levels induced by B[a]P in HPV-positive cells were significantly higher than in HPV-negative cells. The DNA adduct formation was dependent on HPV E6 oncoprotein expression. Gene and protein expression of two DNA repair genes, XRCC3 and XRCC5, were lower in B[a]P-treated E6-positive cells than in E6-negative lung cancer cells. The reduced expression was also detected immunohistochemically and was caused by increased promoter hypermethylation. Moreover, mutations of p53 and epidermal growth factor receptor (EGFR) genes in lung cancer patients were associated with XRCC5 inactivation. In sum, our study indicates that HPV E6-induced promoter hypermethylation of the XRCC3 and XRCC5 DNA repair genes and the resultant decrease in their expression increases B[a]P-induced DNA adducts and contributes to lung tumorigenesis in nonsmokers.


B[a]P; DNA repair; HPV; environmental exposure; promoter hypermethylation

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