Programa de Maestría y Doctorado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510 Ciudad de México, México.
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.
Int J Biol Sci. 2018 Jan 1;14(1):21-35. doi: 10.7150/ijbs.21547. eCollection 2018.
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.
氧化应激被认为是宫颈癌发展的一个风险因素。然而，很少有研究评估与人类乳头瘤病毒（HPV）感染相关的氧化还原状态。本研究旨在确定 HPV 16 型和 18 型的早期表达病毒蛋白 E1、E2、E6 和 E7 以完整形式调节氧化还原状态的作用。因此，分析了异位表达病毒蛋白的上皮细胞中活性氧（ROS）的产生、还原型谷胱甘肽（GSH）的浓度、抗氧化酶过氧化氢酶和超氧化物歧化酶（SOD）的水平和活性以及脱氧核糖核酸（DNA）损伤。我们的研究表明，E6 癌蛋白降低了 GSH 和过氧化氢酶蛋白水平及其酶活性，这与 ROS 产生和 DNA 损伤增加有关。相比之下，E7 癌蛋白增加了 GSH 以及过氧化氢酶蛋白水平及其活性，这与 ROS 减少有关，而不影响 DNA 完整性。E6 和 E7 癌蛋白的共表达中和了每个病毒蛋白独立观察到的作用。此外，E1 和 E2 蛋白的联合表达增加了 ROS 水平，随后增加了 DNA 损伤的标志物磷酸组蛋白 H2AX（γH2AX）。还检测到 E1 和 E2 存在时 GSH 以及 SOD2 水平和活性降低，尽管过氧化氢酶活性增加。本研究表明，HPV 早期表达的蛋白可差异调节细胞氧化还原状态和 DNA 损伤。
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