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

Ya-Wen Cheng,Nan-Yung Hsu,Frank Cheau-Feng Lin,Chih-Yi Chen

doi:10.18632/oncotarget.7628

Abstract

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.

Highlights

Lung cancer is a leading cause of cancer-related deaths in Taiwan as well as in other parts of the world [1,2]
To determine whether the human papillomavirus (HPV)-infected lung tumor cells were more sensitive to benzo(a) pyrene (B[a]P) exposure than the noninfected ones, HPV16-positive and -negative lung cancer cells were treated with low-dose B[a]P, and the DNA adduct levels were detected by ELISA
Cigarette smoke was reported to have a late-stage synergistic effect on cervical carcinogenesis initiated by HPV infection [39]

Summary

Introduction

Lung cancer is a leading cause of cancer-related deaths in Taiwan as well as in other parts of the world [1,2]. The most important risk factor of lung cancer is cigarette smoking [3]. There is evidence of increasing incidence of female lung cancer in Taiwan without a concurrent increase in smoking [2, 4]. It is conceivable that environmental factors other than cigarette smoking may be associated with the development of lung cancer in Taiwan. We observed a high frequency of oncogenic HPV types 16/18 in lung tumor tissues of nonsmoking females [6]. We observed a higherfrequency loss of heterozygosity (LOH) of the fragile histidine triad gene in HPV 16-infected lung tumors of females, suggesting that the HPV involvement in lung tumorigenesis may be mediated through induced chromosome instability [9]

Methods

Results

Conclusion