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Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells

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, ev...

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Autores principales: Muñoz, Juan P., Carrillo-Beltrán, Diego, Aedo-Aguilera, Víctor, Calaf, Gloria M., León, Oscar, Maldonado, Edio, Tapia, Julio C., Boccardo, Enrique, Ozbun, Michelle A., Aguayo, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304352/
https://www.ncbi.nlm.nih.gov/pubmed/30619121
http://dx.doi.org/10.3389/fmicb.2018.03022
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author Muñoz, Juan P.
Carrillo-Beltrán, Diego
Aedo-Aguilera, Víctor
Calaf, Gloria M.
León, Oscar
Maldonado, Edio
Tapia, Julio C.
Boccardo, Enrique
Ozbun, Michelle A.
Aguayo, Francisco
author_facet Muñoz, Juan P.
Carrillo-Beltrán, Diego
Aedo-Aguilera, Víctor
Calaf, Gloria M.
León, Oscar
Maldonado, Edio
Tapia, Julio C.
Boccardo, Enrique
Ozbun, Michelle A.
Aguayo, Francisco
author_sort Muñoz, Juan P.
collection PubMed
description 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.
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spelling pubmed-63043522019-01-07 Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells Muñoz, Juan P. Carrillo-Beltrán, Diego Aedo-Aguilera, Víctor Calaf, Gloria M. León, Oscar Maldonado, Edio Tapia, Julio C. Boccardo, Enrique Ozbun, Michelle A. Aguayo, Francisco Front Microbiol Microbiology 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. Frontiers Media S.A. 2018-12-17 /pmc/articles/PMC6304352/ /pubmed/30619121 http://dx.doi.org/10.3389/fmicb.2018.03022 Text en Copyright © 2018 Muñoz, Carrillo-Beltrán, Aedo-Aguilera, Calaf, León, Maldonado, Tapia, Boccardo, Ozbun and Aguayo. http://creativecommons.org/licenses/by/4.0/ 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.
spellingShingle Microbiology
Muñoz, Juan P.
Carrillo-Beltrán, Diego
Aedo-Aguilera, Víctor
Calaf, Gloria M.
León, Oscar
Maldonado, Edio
Tapia, Julio C.
Boccardo, Enrique
Ozbun, Michelle A.
Aguayo, Francisco
Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells
title Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells
title_full Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells
title_fullStr Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells
title_full_unstemmed Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells
title_short Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells
title_sort tobacco exposure enhances human papillomavirus 16 oncogene expression via egfr/pi3k/akt/c-jun signaling pathway in cervical cancer cells
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304352/
https://www.ncbi.nlm.nih.gov/pubmed/30619121
http://dx.doi.org/10.3389/fmicb.2018.03022
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