Molecular Mechanisms of Human Papillomavirus-Induced Carcinogenesis

Abstract

Approximately 20% of all cancers are associated with infectious agents. Among them, human papillomaviruses (HPVs) are very common and are now recognized as the etiological agent of cervical cancer, the second most common cancer in women worldwide, and they are increasingly linked with other forms of dysplasia. Carcinogenesis is a complex and multistep process requiring the acquisition of several genetic and/or epigenetic alterations. HPV-induced neoplasia, however, is in part mediated by the intrinsic functions of the viral proteins. In order to replicate its genome, HPV modulates the cell cycle, while deploying mechanisms to escape the host immune response, cellular senescence and apoptosis. As such, HPV infection leads directly and indirectly to genomic instability, further favouring transforming genetic events and progression to malignancy. This review aims to summarize our current understanding of the molecular mechanisms exploited by HPV to induce neoplasia, with an emphasis on the role of the 2 viral oncoproteins E6 and E7. Greater understanding of the role of HPV proteins in these processes will ultimately aid in the development of antiviral therapies, as well as unravel general mechanisms of oncogenesis.

Molecular pathogenesis of cervical cancer

“…Also significant are immunosuppression, as seen in Human Immunodeficiency Virus (HIV) co-infection and chronic steroid therapy following organ transplantation, which increase the likelihood of persistence of an oncogenic HPV infection and its sequelae. 6,12 In fact, in HIV patients, cervical cancer is a criterion for making a clinical diagnosis of Acquired Immune Deficiency Syndrome (AIDS).…”

Interplay between genetic and epigenetic factors governs common fragile site instability in cancer

“…Such integrations can act as a causative agent or a cofactor in tumorogenicity. HPV, the most important cancer-related virus, is integrated in the genome of most cervical cancer cells [93]. The first reported HPV integration into a CFS was in FRA3B, near the RCC translocation breakpoint [78].…”

De-oncogenic HPV E6/E7 vaccine gets enhanced antigenicity and promotes tumoricidal synergy with cisplatin

“…HPV16 E6 and E7, and the carcinogenesis of HPV-associated cancers is well established [5,6] and therefore many approaches directly against the viral oncogenes have been reported [7,8]. For instance, E6 can enhance the degradation of p53 and disrupt the function of PTPN13, a cellular phosphatase tumor suppressor; E7 can disable pRb and activates Mi2b [9,10] and Rb can control the activity of E2F transcription factors, which are key regulators of S phase genes.…”