Abstract
The smoking habit is the most important, but not a sufficient cause for lung cancer development. Several studies have reported the human papillomavirus type 16 (HPV16) presence and E6 and E7 transcripts expression in lung carcinoma cases from different geographical regions. The possible interaction between HPV infection and smoke carcinogens, however, remains unclear. In this study we address a potential cooperation between tobacco smoke and HPV16 E6 and E7 oncoproteins for alterations in proliferative and tumorigenic properties of lung epithelial cells. A549 (alveolar, tumoral) and BEAS-2B (bronchial, non-tumoral) cell lines were stably transfected with recombinant pLXSN vectors expressing HPV16 E6 and E7 oncoproteins and exposed to cigarette smoke condensate (CSC) at different concentrations. HPV16 E6 and E7 expression was associated with loss of p53 stability, telomerase (hTERT) and p16INK4A overexpression in BEAS-2B cells as demonstrated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). In A549 cells we observed downregulation of p53 but not a significant increase of hTERT transcripts. In addition, the HPV16 E6/E7 transfected cell lines showed an increased proliferation rate and anchorage-independent growth in a HPV16 E6 and E7 expression-dependent manner. Moreover, both HPV16 E6/E7 and mock transfected cells showed an increased proliferation rate and anchorage-independent growth in the presence of 0.1 and 10 µg/mL CSC. However, this increase was significantly greater in HPV16 E6/E7 transfected cells (p<0.001). Data were confirmed by FCSE proliferation assay. The results obtained in this study are suggestive of a functional interaction between tobacco smoke and HPV16 E6/E7 oncoproteins for malignant transformation and tumorigenesis of lung epithelial cells. More studies are warranted in order to dissect the molecular mechanisms involved in this cooperation.
Highlights
Human Papilloma Virus (HPV) infection and persistence are the necessary conditions for cervix-uterine cancer development [1,2]
The functional activity of the E6 oncoprotein was demonstrated in both cell lines by loss of p53 stability in human papillomavirus type 16 (HPV16) E6 and E6/E7 transfected cells as shown using western blotting (WB) (Fig. 2A)
In addition A549 cells transfected with the HPV16 E7 vector showed p53 up-regulation, demonstrating functional activity of this oncoprotein
Summary
Human Papilloma Virus (HPV) infection and persistence are the necessary conditions for cervix-uterine cancer development [1,2]. It is known that lung cancer development is strongly and directly related to tobacco smoking or cigarette smoke exposition. A very low percentage of heavy smokers develop lung cancer, suggesting that other co-factors are necessary [6]. It has been suggested that HPV has a role as an independent carcinogen when this virus is found in non-smoking subjects, as occurs in women of Taiwan who develop lung adenocarcinomas [7,8]. Other studies have reported a variable presence of HPV in smoking subjects who develop lung cancer [9], the role of HPV in these tumors remains to be elucidated. It is plausible that HPV in these cases might act as a co-carcinogen [10], functional evidence for a potential cooperation between HPV and tobacco smoke for lung tumorigenesis is lacking
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