Human papillomavirus type 18 E5 oncoprotein cooperates with E6 and E7 in promoting cell viability and invasion and in modulating the cellular redox state

Abstract

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.

Nocardia Rubra Cell Wall Skeleton Up-Regulates T Cell Subsets and Inhibits PD-1/PD-L1 Pathway to Promote Local Immune Status of Patients With High-Risk Human Papillomavirus Infection and Cervical Intraepithelial Neoplasia

“…Cervical cancer is still an important cause of mortality among females in developing countries ( 2 ). It has been well known that human papillomavirus (HPVs) are the etiological agents of cervical cancer and its premalignant precursor cervical intraepithelial neoplasia (CIN) ( 3 ). However, not all women who harbor HPV infection will develop cervical cancer.…”

Peroxiredoxins—The Underrated Actors during Virus-Induced Oxidative Stress

“…The uncontradictory data are presented in Table 4 . Pronouncedly increased expression of Prdx1 and Prdx2 occurs in cells overexpression oncoproteins of the high-risk HPV [ 135 , 141 ]. Similar increased content of Prdx1 was noted in the case of overexpression of Epstein–Barr virus (EBV) EBNA1 protein, albeit no changes in its expression occur in such cells [ 142 ].…”

Relationship and prognostic significance of IL-33, PD-1/PD-L1, and tertiary lymphoid structures in cervical cancer

“…1,2 Almost all cervix cancers and its precursor cervical intraepithelial neoplasia are caused by high-risk subtypes of the human papillomavirus (HPV). 3,4 Despite advances in diagnosis and treatments of cervical cancer over the past few years, the recurrence rate and poor prognosis of advanced cervical cancer remains a health challenge. 5 Persistent HPV infection may lead to cytopathic lesions of the cervical cells.…”

“…Cervical cancer is the fourth most common female malignancy worldwide in morbidity, which seriously threatens women's lives and health 1,2 . Almost all cervix cancers and its precursor cervical intraepithelial neoplasia are caused by high‐risk subtypes of the human papillomavirus (HPV) 3,4 . Despite advances in diagnosis and treatments of cervical cancer over the past few years, the recurrence rate and poor prognosis of advanced cervical cancer remains a health challenge 5 .…”