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: Jorge Gutiérrez, Enrique García-Villa, Rodolfo Ocadiz-Delgado, Enoc M Cortés-Malagón, Juan Vázquez, Alejandra Roman-Rosales, Elizabeth Alvarez-Rios, Haydar Celik, Marta C Romano, Aykut Üren, Paul F Lambert, Patricio Gariglio
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 408 Issue 1-2 Pg. 261-72 (Oct 2015) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 26173416 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxamic Acids
• Papillomavirus E7 Proteins
• Receptors, Retinoic Acid
• Tumor Suppressor Protein p53
• oncogene protein E7, Human papillomavirus type 16
• retinoic acid receptor beta
• trichostatin A
• Histone Deacetylases

Topics

• Animals
• Cell Line, Tumor
• Female
• HeLa Cells
• Histone Deacetylases (genetics, metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Mice
• Mice, Transgenic
• Papillomavirus E7 Proteins (metabolism)
• Papillomavirus Infections (genetics, metabolism)
• Receptors, Retinoic Acid (genetics, metabolism)
• Tumor Suppressor Protein p53 (genetics)
• Up-Regulation
• Uterine Cervical Neoplasms (genetics, metabolism, virology)