Original Research ARTICLE
Tobacco exposure enhances human papillomavirus 16 oncogene expression via EGFR/PI3K/Akt/c-Jun signaling pathway in cervical cancer cells
- 1Departamento de Oncología Básico Clínica, Universidad de Chile, Chile
- 2Programa de Biología Celular y Molecular, Universidad de Chile, Chile
- 3Columbia University, United States
- 4Programa de Virología, Universidad de Chile, Chile
- 5Department of Microbiology, University of São Paulo, Brazil
- 6Department of Molecular Genetics and Microbiology, University of New Mexico, United States
- 7Centro de Estudios Avanzados de Enfermedades Crónicas (ACCDiS), Chile
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 c-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.
Keywords: cervical cancer, papillomavirus, cigarette smoke, signaling, HPV oncoproteins
Received: 01 Jun 2018;
Accepted: 22 Nov 2018.
Edited by:Benjamin Lopman, Emory University, United States
Reviewed by:Roxana Pincheira, Universidad de Concepción, Chile
Lorena L. Lobos-Gonzalez, Facultad de Medicina Clinica Alemana, Universidad del Desarrollo, Chile
Copyright: © 2018 Muñoz, Carrillo, Aedo-Aguilera, Calaf, León, Maldonado, Tapia, Boccardo, Ozbun and Aguayo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Dr. Francisco Aguayo, Universidad de Chile, Departamento de Oncología Básico Clínica, Independencia 1027, Santiago, 8389100, RM, Chile, firstname.lastname@example.org