Oxidative stress and HPV carcinogenesis

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.

Figure 1

Lewis formulas of reactive oxygen and nitrogen species and structural formulas of lipid peroxidation products responsible for DNA modifications with miscoding potentials.

Figure 2

Major base lesions induced by OS.

Figure 3

OS and viral DNA replication conceptual map. OS and viral oncogenes concur to create a cellular environment conducive to viral genome amplification and integration. E2 and TopBP1 interact in vitro and in vivo and TopBP1 enhance the ability of E2 to activate transcription and replication [68]. The E6-dependent p53 degradation abolishes BER functions leading to unrepaired cellular genome [69,70]. The E7 protein promote the phosphorylation of the inactive ATM dimer causing its dissociation into phosphorilated active monomers. The E7 protein then physically interact with the activated ATM monomer activating a number of proteins including CHK2, BRCA1 and NSB1. CHK2 induce proteolytic activation of Caspase 3/7, cleaving the E1 protein, and enhancing the E1 binding to its origin and its ability to replicate in an E2-independent manner [71]. The E7 oncoprotein attenuates the DNA damage checkpoint response by accelerating the proteolytic turnover of claspin, a critical regulator of the ATR/CHK1 signaling axis, in the G2 phase of the cell cycle [72]. These conditions permit the formation of abundant regular and rearranged viral copies, while multiple nicks and DS breaks in the host genome are unrepaired, thus creating the mechanistic feasibility for multiple viral integrations.