title: Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice.
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.
authors.affiliation: 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.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gutiérrez
authors.affiliation: 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.
authors.forename: Enrique
authors.initials: E
authors.lastname: García-Villa
authors.affiliation: 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.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Ocadiz-Delgado
authors.affiliation: 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.
authors.forename: Enoc M
authors.initials: EM
authors.lastname: Cortés-Malagón
authors.affiliation: 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.
authors.forename: Juan
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: 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.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Roman-Rosales
authors.affiliation: 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Alvarez-Rios
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057-1469, USA.
authors.forename: Haydar
authors.initials: H
authors.lastname: Celik
authors.affiliation: 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.
authors.forename: Marta C
authors.initials: MC
authors.lastname: Romano
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20057-1469, USA.
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53706, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
authors.affiliation: 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. vidal@cinvestav.mx.
authors.forename: Patricio
authors.initials: P
authors.lastname: Gariglio
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology*
chemical_list: D006877:Hydroxamic Acids; D050725:Papillomavirus E7 Proteins; D018168:Receptors, Retinoic Acid; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16; C082925:retinoic acid receptor beta; C012589:trichostatin A; D006655:Histone Deacetylases
keywords: Cervical cancer; HDACs; HPV16 E7 oncoprotein; RARB; TP53 R273C mutant