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

Juan P. Muñoz; Diego Carrillo-Beltrán; Víctor Aedo-Aguilera; Gloria M. Calaf; Oscar León; Edio Maldonado; Julio C. Tapia; Enrique Boccardo; Michelle A. Ozbun; Francisco Aguayo

doi:10.3389/fmicb.2018.03022

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

Título traducido de la contribución: La exposición al tabaco potencia la expresión del oncogén 16 del virus del papiloma humano a través de la vía de señalización EGFR/PI3K/Akt/c-Jun en células de cáncer cervical.

Juan P. Muñoz
, Diego Carrillo-Beltrán
, Víctor Aedo-Aguilera
, Gloria M. Calaf
, Oscar León
, Edio Maldonado
, Julio C. Tapia
, Enrique Boccardo
, Michelle A. Ozbun
, Francisco Aguayo

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

46 Citas (Scopus)

Resumen

La infección por el virus del papiloma humano de alto riesgo (VPH-AR) no es condición suficiente para el desarrollo del cáncer de cuello uterino, ya que la mayoría de las infecciones son benignas y se resuelven espontáneamente. Estudios epidemiológicos han revelado que el tabaquismo es un cofactor del VPH-AR para la iniciación y progresión del cáncer de cuello uterino, si bien el mecanismo por el cual el humo del tabaco interactúa con el VPH-AR en esta neoplasia maligna aún no se comprende del todo. Dado que las oncoproteínas E6/E7 del VPH-AR, sobreexpresadas en carcinomas cervicales, se localizan junto con componentes del humo del cigarrillo (CSC), en este estudio analizamos las vías de señalización implicadas en una posible interacción entre ambos agentes carcinógenos. Las líneas celulares derivadas de cáncer de cuello uterino CaSki (VPH16; 500 copias por célula) y SiHa (VPH16; 2 copias por célula) se expusieron de forma aguda a CSC en diversas concentraciones no tóxicas, y observamos que los niveles de E6 y E7 aumentaron significativamente de forma dosis-dependiente. Utilizando un constructo reportero que contenía el gen de la luciferasa bajo el control de la región de control larga (LCR) completa del VPH16, también encontramos que la actividad del promotor p97 depende de CSC. Las mutaciones no sinónimas en los elementos de respuesta a TPA (12-O-tetradecanoilforbol 13-acetato) (TRE) presentes en la LCR disminuyeron significativamente la activación del promotor p97. Los análisis fosfoproteómicos y el uso de inhibidores específicos revelaron que la sobreexpresión de E6/E7 mediada por CSC depende, al menos en parte, de la fosforilación del EGFR. Además, demostramos que la vía PI3K/Akt es crucial para la sobreexpresión de E6/E7 inducida por CSC. Finalmente, demostramos que la sobreexpresión de E6/E7 del VPH16 está mediada por la sobreexpresión de JUN, la fosforilación de c-Jun y el reclutamiento de este factor de transcripción a los sitios TRE en la LCR del VPH16. Concluimos que la exposición aguda al humo del tabaco activa la transcripción de los oncogenes HPV16 E6 y E7 a través de la activación del promotor p97, lo que implica la activación de la vía de señalización EGFR/PI3K/Akt/C-Jun en las células de cáncer cervical.

Título traducido de la contribución	La exposición al tabaco potencia la expresión del oncogén 16 del virus del papiloma humano a través de la vía de señalización EGFR/PI3K/Akt/c-Jun en células de cáncer cervical.
Idioma original	Inglés
Número de artículo	3022
Publicación	Frontiers in Microbiology
Volumen	9
DOI	https://doi.org/10.3389/fmicb.2018.03022
Estado	Publicada - 17 dic. 2018

Palabras clave

Oncoproteínas del VPH
Cáncer de cuello uterino
Humo de cigarrillo
Papilomavirus
Señalización

ODS de las Naciones Unidas

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10.3389/fmicb.2018.03022Licencia: CC BY

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Muñoz, J. P., Carrillo-Beltrán, D., Aedo-Aguilera, V., Calaf, G. M., León, O., Maldonado, E., Tapia, J. C., Boccardo, E., Ozbun, M. A., & Aguayo, F. (2018). Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells. Frontiers in Microbiology, 9, Artículo 3022. https://doi.org/10.3389/fmicb.2018.03022

@article{78db2e7faffd400488860eff3cc5b7cc,

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

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.",

keywords = "HPV oncoproteins, cervical cancer, cigarette smoke, papillomavirus, signaling, Oncoprote{\'i}nas del VPH, C{\'a}ncer de cuello uterino, Humo de cigarrillo, Papilomavirus, Se{\~n}alizaci{\'o}n",

author = "Mu{\~n}oz, \{Juan P.\} and Diego Carrillo-Beltr{\'a}n and V{\'i}ctor Aedo-Aguilera and Calaf, \{Gloria M.\} and Oscar Le{\'o}n and Edio Maldonado and Tapia, \{Julio C.\} and Enrique Boccardo and Ozbun, \{Michelle A.\} and Francisco Aguayo",

note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2018 Mu{\~n}oz, Carrillo-Beltr{\'a}n, Aedo-Aguilera, Calaf, Le{\'o}n, Maldonado, Tapia, Boccardo, Ozbun and Aguayo.",

year = "2018",

month = dec,

day = "17",

doi = "10.3389/fmicb.2018.03022",

language = "English",

volume = "9",

journal = "Frontiers in Microbiology",

issn = "1664-302X",

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TY - JOUR

T1 - Tobacco Exposure Enhances Human Papillomavirus 16 Oncogene Expression via EGFR/PI3K/Akt/c-Jun Signaling Pathway in Cervical Cancer Cells

AU - Muñoz, Juan P.

AU - Carrillo-Beltrán, Diego

AU - Aedo-Aguilera, Víctor

AU - Calaf, Gloria M.

AU - León, Oscar

AU - Maldonado, Edio

AU - Tapia, Julio C.

AU - Boccardo, Enrique

AU - Ozbun, Michelle A.

AU - Aguayo, Francisco

PY - 2018/12/17

Y1 - 2018/12/17

N2 - 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.

AB - 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.

KW - HPV oncoproteins

KW - cervical cancer

KW - cigarette smoke

KW - papillomavirus

KW - signaling

KW - Oncoproteínas del VPH

KW - Cáncer de cuello uterino

KW - Humo de cigarrillo

KW - Papilomavirus

KW - Señalización

UR - https://www.scopus.com/pages/publications/85078675406

U2 - 10.3389/fmicb.2018.03022

DO - 10.3389/fmicb.2018.03022

M3 - Article

AN - SCOPUS:85078675406

SN - 1664-302X

VL - 9

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

M1 - 3022

ER -

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

Resumen

Palabras clave

ODS de las Naciones Unidas

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