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...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-12-01
|
| Series: | Frontiers in Microbiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2018.03022/full |
| _version_ | 1818179890267029504 |
|---|---|
| author | Juan P. Muñoz Diego Carrillo-Beltrán Víctor Aedo-Aguilera Gloria M. Calaf Gloria M. Calaf Oscar León Edio Maldonado Julio C. Tapia Enrique Boccardo Michelle A. Ozbun Francisco Aguayo Francisco Aguayo Francisco Aguayo |
| author_facet | Juan P. Muñoz Diego Carrillo-Beltrán Víctor Aedo-Aguilera Gloria M. Calaf Gloria M. Calaf Oscar León Edio Maldonado Julio C. Tapia Enrique Boccardo Michelle A. Ozbun Francisco Aguayo Francisco Aguayo Francisco Aguayo |
| author_sort | Juan P. Muñoz |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T21:11:03Z |
| format | Article |
| id | doaj.art-599709c82e1746a78c48ca98fe24613d |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-11T21:11:03Z |
| publishDate | 2018-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-599709c82e1746a78c48ca98fe24613d2022-12-22T00:50:44ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2018-12-01910.3389/fmicb.2018.03022403932Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer CellsJuan P. Muñoz0Diego Carrillo-Beltrán1Víctor Aedo-Aguilera2Gloria M. Calaf3Gloria M. Calaf4Oscar León5Edio Maldonado6Julio C. Tapia7Enrique Boccardo8Michelle A. Ozbun9Francisco Aguayo10Francisco Aguayo11Francisco Aguayo12Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, ChileDepartamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, ChileDepartamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, ChileCenter for Advanced Research, Tarapaca University, Arica, ChileCenter for Radiological Research, Columbia University Medical Center, New York, NY, United StatesVirology Program, Instituto de Ciencias Biomédicas, Faculty of Medicine, University of Chile, Santiago, ChilePrograma Biología Celular y Molecular, Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, ChileDepartamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, ChileDepartment of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, BrazilDepartment of Molecular Genetics and Microbiology, The University of New Mexico School of Medicine, Albuquerque, NM, United StatesDepartamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, ChileCenter for Advanced Research, Tarapaca University, Arica, ChileAdvanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, University of Chile, Santiago, ChileHigh-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.https://www.frontiersin.org/article/10.3389/fmicb.2018.03022/fullcervical cancerpapillomaviruscigarette smokesignalingHPV oncoproteins |
| spellingShingle | Juan P. Muñoz Diego Carrillo-Beltrán Víctor Aedo-Aguilera Gloria M. Calaf Gloria M. Calaf Oscar León Edio Maldonado Julio C. Tapia Enrique Boccardo Michelle A. Ozbun Francisco Aguayo Francisco Aguayo Francisco Aguayo Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells Frontiers in Microbiology cervical cancer papillomavirus cigarette smoke signaling HPV oncoproteins |
| 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 | cervical cancer papillomavirus cigarette smoke signaling HPV oncoproteins |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2018.03022/full |
| work_keys_str_mv | AT juanpmunoz tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT diegocarrillobeltran tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT victoraedoaguilera tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT gloriamcalaf tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT gloriamcalaf tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT oscarleon tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT ediomaldonado tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT julioctapia tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT enriqueboccardo tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT michelleaozbun tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT franciscoaguayo tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT franciscoaguayo tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells AT franciscoaguayo tobaccoexposureenhanceshumanpapillomavirus16oncogeneexpressionviaegfrpi3kaktcjunsignalingpathwayincervicalcancercells |