BACKGROUND High-risk human papillomaviruses (HR-HPVs) are the etiological agents of cervical cancer. Among them, types 16 and 18 are the most prevalent worldwide. The HPV genome encodes three oncoproteins (E5, E6, and E7) that possess a high transformation potential in culture cells when transduced simultaneously. In the present study, we analysed how these oncoproteins cooperate to boost key cancer cell features such as uncontrolled cell proliferation, invasion potential, and cellular redox state imbalance. Oxidative stress is known to contribute to the carcinogenic process, as reactive oxygen species (ROS) constitute a potentially harmful by-product of many cellular reactions, and an efficient clearance mechanism is therefore required. Cells infected with HR-HPVs can adapt to oxidative stress conditions by upregulating the formation of endogenous antioxidants such as catalase, glutathione (GSH), and peroxiredoxin (PRX). OBJECTIVES The primary aim of this work was to study how these oncoproteins cooperate to promote the development of certain cancer cell features such as uncontrolled cell proliferation, invasion potential, and oxidative stress that are known to aid in the carcinogenic process. METHODS To perform this study, we generated three different HaCaT cell lines using retroviral transduction that stably expressed combinations of HPV-18 oncogenes that included HaCaT E5-18, HaCaT E6/E7-18, and HaCaT E5/E6/E7-18. FINDINGS Our results revealed a statistically significant increment in cell viability as measured by MTT assay, cell proliferation, and invasion assays in the cell line containing the three viral oncogenes. Additionally, we observed that cells expressing HPV-18 E5/E6/E7 exhibited a decrease in catalase activity and a significant augmentation of GSH and PRX1 levels relative to those of E5, E6/E7, and HaCaT cells. MAIN CONCLUSIONS This study demonstrates for the first time that HPV-18 E5, E6, and E7 oncoproteins can cooperate to enhance malignant transformation.

中文翻译：

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人类乳头瘤病毒18型E5癌蛋白与E6和E7协同作用，促进细胞活力和侵袭并调节细胞氧化还原状态

背景技术高危的人乳头瘤病毒（HR-HPV）是宫颈癌的病因。其中，类型16和18是全球最流行的类型。HPV基因组编码三种癌蛋白（E5，E6和E7），当同时转导时，它们在培养细胞中具有很高的转化潜能。在本研究中，我们分析了这些癌蛋白如何协同作用来增强关键的癌细胞特征，例如不受控制的细胞增殖，侵袭潜力和细胞氧化还原状态的失衡。众所周知，氧化应激会导致致癌过程，因为活性氧（ROS）构成了许多细胞反应的潜在有害副产物，因此需要有效的清除机制。感染HR-HPV的细胞可通过上调过氧化氢酶，谷胱甘肽（GSH）和过氧化物酶（PRX）等内源性抗氧化剂的形成来适应氧化应激条件。目的这项工作的主要目的是研究这些癌蛋白如何协同促进某些癌细胞特征的发展，例如不受控制的细胞增殖，侵袭潜能和氧化应激，这些都有助于致癌过程。方法为了进行这项研究，我们使用逆转录病毒转导产生了三种不同的HaCaT细胞系，该系稳定表达HPV-18癌基因的组合，包括HaCaT E5-18，HaCaT E6 / E7-18和HaCaT E5 / E6 / E7-18。结果我们的结果显示，通过MTT分析，细胞增殖，含有三种病毒癌基因的细胞系中的侵袭和侵袭试验。此外，我们观察到，相对于E5，E6 / E7和HaCaT细胞，表达HPV-18 E5 / E6 / E7的细胞表现出过氧化氢酶活性降低，GSH和PRX1水平显着增加。主要结论这项研究首次证明HPV-18 E5，E6和E7癌蛋白可以协同增强恶性转化。