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Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice

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Abstract

Persistent infection with high-risk human papillomaviruses is the main etiological factor in cervical cancer (CC). The human papillomavirus type 16 (HPV16) E7 oncoprotein alters several cellular processes, regulating the expression of many genes in order to avoid cell cycle control. Retinoic acid receptor beta (RARB) blocks cell growth, inducing differentiation and apoptosis. This tumor suppressor gene is gradually silenced in late passages of foreskin keratinocytes immortalized with HPV16 and in various tumors, including CC, mainly by epigenetic modifications. We investigated the effect of E7 oncoprotein on RARB gene expression. We found that HPV16 E7 increases RARB mRNA and RAR-beta protein expression both in vitro and in the cervix of young K14E7 transgenic mice. In E7-expressing cells, RARB overexpression is further increased in the presence of the tumor suppressor p53 (TP53) R273C mutant. This effect does not change when either C33-A or E7-expressing C33-A cell line is treated with Trichostatin A, suggesting that E7 enhances RARB expression independently of histone deacetylases inhibition. These findings indicate that RARB overexpression is part of the early molecular events induced by the E7 oncoprotein.

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Acknowledgments

The authors would like to thank CONACYT, Lauro Macías, and Gabriela Mora (CINVESTAV-IPN) for technical support.

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Authors and Affiliations

  1. Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. IPN 2508, San Pedro Zacatenco, Gustavo A. Madero, 07360, Ciudad de México, México

    Jorge Gutiérrez, Enrique García-Villa, Rodolfo Ocadiz-Delgado, Juan Vázquez, Alejandra Roman-Rosales, Elizabeth Alvarez-Rios & Patricio Gariglio

  2. Laboratorio de Biología Molecular del Cáncer, Unidad de Investigación, Hospital Juárez de México, Av. IPN 5160, Magdalena de Las Salinas, Gustavo A. Madero, 07760, Ciudad de México, México

    Enoc M. Cortés-Malagón

  3. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057-1469, USA

    Haydar Celik & Aykut Üren

  4. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. IPN 2508, San Pedro Zacatenco, Gustavo A. Madero, 07360, Ciudad de México, México

    Marta C. Romano

  5. McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53706, USA

    Paul F. Lambert

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  1. Jorge Gutiérrez
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Gutiérrez, J., García-Villa, E., Ocadiz-Delgado, R. et al. Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice. Mol Cell Biochem 408, 261–272 (2015). https://doi.org/10.1007/s11010-015-2504-1

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