Abstract
Extensive experimental work has conclusively demonstrated that infection with certain types of human papillomaviruses, the so-called high-risk human papillomavirus (HR-HPV), represent a most powerful human carcinogen. However, neoplastic growth is a rare and inappropriate outcome in the natural history of HPV, and a number of other events have to concur in order to induce the viral infection into the (very rare) neoplastic transformation. From this perspective, a number of putative viral, host, and environmental co-factors have been proposed as potential candidates. Among them oxidative stress (OS) is an interesting candidate, yet comparatively underexplored. OS is a constant threat to aerobic organisms being generated during mitochondrial oxidative phosphorylation, as well as during inflammation, infections, ionizing irradiation, UV exposure, mechanical and chemical stresses. Epithelial tissues, the elective target for HPV infection, are heavily exposed to all named sources of OS. Two different types of cooperative mechanisms are presumed to occur between OS and HPV: I) The OS genotoxic activity and the HPV-induced genomic instability concur independently to the generation of the molecular damage necessary for the emergence of neoplastic clones. This first mode is merely a particular form of co-carcinogenesis; and II) OS specifically interacts with one or more molecular stages of neoplastic initiation and/or progression induced by the HPV infection. This manuscript was designed to summarize available data on this latter hypothesis. Experimental data and indirect evidences on promoting the activity of OS in viral infection and viral integration will be reviewed. The anti-apoptotic and pro-angiogenetic role of NO (nitric oxide) and iNOS (inducible nitric oxide synthase) will be discussed together with the OS/HPV cooperation in inducing cancer metabolism adaptation. Unexplored/underexplored aspects of the OS interplay with the HPV-driven carcinogenesis will be highlighted. The aim of this paper is to stimulate new areas of study and innovative approaches.
Highlights
Cervical cancer is one of the leading causes of cancer death among women
Indirect clinical epidemiological evidence and initial biochemical data support the conclusion that viral infection, establishment of persistent-chronicle infection, and viral integration are potentiated by oxidative stress (OS)
Both pro-survival and pro-apoptotic mechanisms have been described for OS; in viral dysplastic lesions, OS behaves as a pro-survival factor promoting the AP-1 mediated expression of E6 and E7, reinforcing their anti-apoptotic mechanisms
Summary
Cervical cancer is one of the leading causes of cancer death among women. The identification of HR-HPV infection as the etiologic agents of cervical cancer, as well as other non-genital carcinomas, is undoubtedly among the greatest medical advances that have been made in the last twenty years [1]. According to a widely shared view, these viruses must induce an enhanced proliferative state in order to accomplish their replicative cycle in the poorly replicating host epithelial cell This is achieved through the activity of two oncogenic proteins, E6 and E7. Through the perturbation of the cellular redox balance, they induce the activation of several redox-sensitive transcription factors, modify the gene expression responses, and modulate the function of redox-sensitive proteins They have been implicated in various acute or chronic degenerative processes, including aging and cancer [11,12,13]. Due to their conspicuous impact on cell homeostasis, RONS levels are closely monitored by sophisticated sensing mechanisms and are strictly controlled by multiple antioxidant and scavenging systems. This paper was designed to provide a brief description of RONS generation and their biological impact, to summarize available data on the impact OS has on the major stages of HPV-mediated carcinogenesis, and to promote the identification of new areas of study and innovative approaches
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