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Int J Biol Sci 2018; 14(1):21-35. doi:10.7150/ijbs.21547

Research Paper

Human Papillomavirus Types 16 and 18 Early-expressed Proteins Differentially Modulate the Cellular Redox State and DNA Damage

Alfredo Cruz-Gregorio1,2, Joaquín Manzo-Merino3, María Cecilia Gonzaléz-García1,2, José Pedraza-Chaverri4, Omar Noel Medina-Campos4, Mahara Valverde5, Emilio Rojas5, María Alexandra Rodríguez-Sastre5, Claudia María García-Cuellar2, Marcela Lizano2,5✉

1. Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 Ciudad de México, México;
2. Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología, México/Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México. San Fernando No. 22, Col. Sección XVI, Tlalpan, 14080 Ciudad de México, México;
3. CONACyT Research Fellow, Instituto Nacional de Cancerología, San Fernando No. 22, Col. Sección XVI, Tlalpan, México;
4. Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 Ciudad de México, México;
5. Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Ciudad de México, México.

Abstract

Oxidative stress has been proposed as a risk factor for cervical cancer development. However, few studies have evaluated the redox state associated with human papillomavirus (HPV) infection. The aim of this work was to determine the role of the early expressed viral proteins E1, E2, E6 and E7 from HPV types 16 and 18 in the modulation of the redox state in an integral form. Therefore, generation of reactive oxygen species (ROS), concentration of reduced glutathione (GSH), levels and activity of the antioxidant enzymes catalase and superoxide dismutase (SOD) and deoxyribonucleic acid (DNA) damage, were analysed in epithelial cells ectopically expressing the viral proteins. Our research shows that E6 oncoproteins decreased GSH and catalase protein levels, as well as its enzymatic activity, which was associated with an increase in ROS production and DNA damage. In contrast, E7 oncoproteins increased GSH, as well as catalase protein levels and its activity, which correlated with a decrease in ROS without affecting DNA integrity. The co-expression of both E6 and E7 oncoproteins neutralized the effects that were independently observed for each of the viral proteins. Additionally, the combined expression of E1 and E2 proteins increased ROS levels with the subsequent increase in the marker for DNA damage phospho-histone 2AX (γH2AX). A decrease in GSH, as well as SOD2 levels and activity were also detected in the presence of E1 and E2, even though catalase activity increased. This study demonstrates that HPV early expressed proteins differentially modulate cellular redox state and DNA damage.

Keywords: Human papillomavirus early-expressed proteins, redox state, ROS, catalase, SOD1/2, GSH, DNA damage.

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How to cite this article:
Cruz-Gregorio A, Manzo-Merino J, Gonzaléz-García MC, Pedraza-Chaverri J, Medina-Campos ON, Valverde M, Rojas E, Rodríguez-Sastre MA, García-Cuellar CM, Lizano M. Human Papillomavirus Types 16 and 18 Early-expressed Proteins Differentially Modulate the Cellular Redox State and DNA Damage. Int J Biol Sci 2018; 14(1):21-35. doi:10.7150/ijbs.21547. Available from http://www.ijbs.com/v14p0021.htm