The Not-So-Good, the Bad and the Ugly: HPV E5, E6 and E7 Oncoproteins in the Orchestration of Carcinogenesis

Abstract

Infection with HPV starts with the access of the viral particles to basal cells in the epidermis, potentially via microtraumas to the skin. The basal cells are able to keep away these pathogens in normal circumstances through a robust immune response from the host, as HPV infections are, in general, cleared within 2 to 3 weeks. However, the rare instances of persistent infection and/or in cases where the host immune system is compromised are major risk factors for the development of lesions potentially leading to malignancy. Evolutionarily, obligatory pathogens such as HPVs would not be expected to risk exposing the host to lethal cancer, as this would entail challenging their own life cycle, but infection with these viruses is highly correlated with cancer and malignancy—as in cancer of the cervix, which is almost always associated with these viruses. Despite this key associative cause and the availability of very effective vaccines against these viruses, therapeutic interventions against HPV-induced cancers are still a challenge, indicating the need for focused translational research. In this review, we will consider the key roles that the viral proteins play in driving the host cells to carcinogenesis, mainly focusing on events orchestrated by early proteins E5, E6 and E7—the not-so-good, the bad and the ugly—and discuss and summarize the major events that lead to these viruses mechanistically corrupting cellular homeostasis, giving rise to cancer and malignancy.

Infection by High-Risk Human Papillomaviruses, Epithelial-to-Mesenchymal Transition and Squamous Pre-Malignant or Malignant Lesions of the Uterine Cervix: A Series of Chained Events?

“…At the same time, E5 inhibits epithelial cell differentiation by downregulating the expression of the fibroblast growth factor receptor (FGFR)2b [68][69][70]. Because of all these activities, E5 favors the proliferation of immature basal cells and, at the same time, hampers their differentiation (Table 1) [68][69][70]. The findings summarized herein are from references [68][69][70].…”

“…Once sexually transmitted, HR-HPVs reach the cells of the basal layer of the ectocervical epithelium: there the viruses actively replicate, this implying the expression of the viral genome and the synthesis of its products, the E5, E6, and E7 transforming proteins included [62][63][64][65][66][67][68][69].…”

“…In the epithelial cells of the uterine cervix basal layer, E5 increases the protein levels of the receptor for the highly mitogenic epidermal growth factor (EGF) via a block of its degradation that normally follows its stimulation by EGF [68,69]. In addition, E5 enhances the mitogenic activity of endothelin-1 and downregulates the expression of the cyclindependent protein kinase inhibitors p21 WAF/CIP1 and p27 KIP1 , thus promoting cell cycle progression [69]. Furthermore, E5 hampers the adhesive interactions among epithelial cells mediated by connexin 43: this reduces the contact inhibition, further contributing to the proliferation of epithelial cells [68].…”

“…Furthermore, E5 hampers the adhesive interactions among epithelial cells mediated by connexin 43: this reduces the contact inhibition, further contributing to the proliferation of epithelial cells [68]. At the same time, E5 inhibits epithelial cell differentiation by downregulating the expression of the fibroblast growth factor receptor (FGFR)2b [68][69][70]. Because of all these activities, E5 favors the proliferation of immature basal cells and, at the same time, hampers their differentiation (Table 1) [68][69][70].…”

It Takes Two to Tango: A Review of Oncogenic Virus and Host Microbiome Associated Inflammation in Head and Neck Cancer

“…Inhibition of MAPK by E7 can also impede epithelial differentiation, contributing to mutagenesis. Together, E6 and E7 promote chromosome instability and inhibit apoptosis [71].…”