Abstract
High-risk human papillomavirus (HR-HPV) infection is not a sufficient condition for cervical cancer development because most infections are benign and naturally cleared. Epidemiological studies revealed that tobacco smoking is a cofactor with HR-HPV for cervical cancer initiation and progression, even though the mechanism by which tobacco smoke cooperates with HR-HPV in this malignancy is poorly understood. As HR-HPV E6/E7 oncoproteins overexpressed in cervical carcinomas colocalize with cigarette smoke components (CSC), in this study we addressed the signaling pathways involved in a potential interaction between both carcinogenic agents. Cervical cancer-derived cell lines, CaSki (HPV16; 500 copies per cell) and SiHa (HPV16; 2 copies per cell), were acutely exposed to CSC at various non-toxic concentrations and we found that E6 and E7 levels were significantly increased in a dose-dependent manner. Using a reporter construct containing the luciferase gene under the control of the full HPV16 long control region (LCR), we also found that p97 promoter activity is dependent on CSC. Non-synonymous mutations in the LCR-resident TPA (12-O-tetradecanoylphorbol 13-acetate)-response elements (TRE) had significantly decreased p97 promoter activation. Phosphoproteomic arrays and specific inhibitors revealed that CSC-mediated E6/E7 overexpression is at least in part reliant on EGFR phosphorylation. In addition, we showed that the PI3K/Akt pathway is crucial for CSC-induced E6/E7 overexpression. Finally, we demonstrated that HPV16 E6/E7 overexpression is mediated by JUN. overexpression, c-Jun phosphorylation and recruitment of this transcription factor to TRE sites in the HPV16 LCR. We conclude that acute exposure to tobacco smoke activates the transcription of HPV16 E6 and E7 oncogenes through p97 promoter activation, which involves the EGFR/PI3K/Akt/C-Jun signaling pathway activation in cervical cancer cells.
Highlights
Human papillomaviruses (HPV) are small and naked DNA viruses with tropism for squamous stratified epithelia where it replicates and establishes either acute and persistent infections
Human papillomaviruses gene expression is regulated by a long control region (LCR) which contains an enhancer motif where cellular and viral proteins bind to cognate binding sites and regulate the activity of the early promoter, located next to the E6 start codon (Chow et al, 2010)
It has been clearly established that highrisk HPV (HR-HPV) infection is not a sufficient condition for cervical cancer development (Schiffman et al, 2007)
Summary
Human papillomaviruses (HPV) are small and naked DNA viruses with tropism for squamous stratified epithelia where it replicates and establishes either acute and persistent infections (zur Hausen, 2002). Human papillomaviruses gene expression is regulated by a long control region (LCR) which contains an enhancer motif where cellular and viral proteins bind to cognate binding sites and regulate the activity of the early promoter, located next to the E6 start codon (nucleotide 97 in HPV16 and 105 in HPV18) (Chow et al, 2010). E6 and E7 oncoproteins, through their abilities to interact with different cellular protein partners, are required for cervical cancer development, other cofactors are necessary for establishment and progression to cancer (White et al, 2012) Both host and environmental factors are relevant for increasing the transformation properties of HR-HPV oncoproteins (Castellsagué and Muñoz, 2003). We found that PI3K/Akt signaling pathway is critical for tobacco smoke-mediated E6 and E7 overexpression
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