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.
Highlights
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This phenocopies the effect of expressing high-risk human papillomavirus (HPV)-16 E7, which inhibits differentiation upon cell detachment and allows cells to proliferate in suspension, suggesting that targeting PTPN14 by high-risk E7 through p600 allows E7-expressing cells to survive anoikis and proliferate, irrespective of their anchorage to the basement membrane [206,207], a characteristic hallmark of cancer cells in resisting cell death
HPV-16 E6 expression was shown to sustain the activation of receptor protein tyrosine kinases, including epidermal growth factor receptor (EGFR), insulin receptor beta, and insulin-like growth factor receptor beta, mediated via the signalling adaptor protein Growth Factor Receptor-Bound protein 2 (GRB2), which is upstream of the PI3K/AKT pathway [233]
Summary
The cellular transforming activity of high-risk HPV genomes was established in the mid-1980s in rodent cell line transformation assays [54,78], and subsequently, E7 was recognized as the major transforming protein of high-risk HPVs, using mutational analyses in transformation assays [52,79,80,81,82,83,84]. Co-transformation assays in murine kidney cells and human mammary epithelial cells established that HPV-16 E6 has transforming properties, inducing anchorage-independent growth and tumour formation in nude mice [95,96]; low-risk E6 were unable to do so [97]. Both E6 and E7 cooperate in transformation, where E7 drives the early tumourigenesis and E6 modulates the progression towards malignancy [90,98]. Upon integration of the HPV genome in high-risk HPV-18, E5 is often disrupted; in the case of HPV-16-positive cervical and oropharyngeal cancers, the expression of E5 is more likely and has been shown to be detectable [111,112,113,114,115], suggesting that E5 may contribute to malignant progression of the cancer
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