What are the essential determinants of human papillomavirus carcinogenesis?

Abstract

Human papillomavirus (HPV) infection is the leading viral cause of cancer. Over the past several decades, research on HPVs has provided remarkable insight into human cell biology and into the pathology of viral and non-viral cancers. The HPV E6 and E7 proteins engage host cellular proteins to establish an environment in infected cells that is conducive to virus replication. They rewire host cell signaling pathways to promote proliferation, inhibit differentiation, and limit cell death. The activity of the "high-risk" HPV E6 and E7 proteins is so potent that their dysregulated expression is sufficient to drive the initiation and maintenance of HPV-associated cancers. Consequently, intensive research efforts have aimed to identify the host cell targets of E6 and E7, in part with the idea that some or all of the virus-host interactions would be essential cancer drivers. These efforts have identified a large number of potential binding partners of each oncoprotein. However, over the same time period, parallel research has revealed that a relatively small number of genetic mutations drive carcinogenesis in most non-viral cancers. We therefore propose that a high-priority goal is to identify which of the many targets of E6 and E7 are critical drivers of HPV carcinogenesis. By identifying the cancer-driving targets of E6 and E7, it should be possible to better understand the distinct roles of other targets, perhaps in the viral life cycle, and to focus efforts to develop anti-cancer therapies on the subset of virus-host interactions for which therapeutic intervention would have the greatest impact.

Keywords: carcinogenesis; host-cell interactions; papillomavirus; transformation.

Fig 1

Carcinogenic activities of high-risk HPV E6 and E7. Several activities of the high-risk HPV E6 and E7 oncoproteins are well-established contributors to carcinogenesis. Diverse HPV E7 proteins recruit the ubiquitin ligase UBR4 to degrade the tumor suppressor PTPN14, activating the YAP1 oncoprotein and increasing the propensity of keratinocytes to adopt a basal cell identity. High-risk HPV E7 proteins bind and degrade the retinoblastoma tumor suppressor (pRB), which activates E2F-dependent transcription and drives aberrant proliferation. pRB degradation is also likely to inhibit non-canonical (E2F-independent) activities of pRB. High-risk HPV E7 proteins also stabilize the tumor suppressor p53. Increased p53 levels sensitize cells to p53-dependent cell death that is inhibited by the activity of high-risk HPV E6 proteins, which recruit the ubiquitin ligase E6AP to target p53 for proteasome-mediated degradation, thereby promoting unchecked keratinocyte proliferation. High-risk HPV E6 proteins also increase transcription of the catalytic subunit of human telomerase (TERT), enabling indefinite keratinocyte proliferation. High-risk HPV E6 and E7 proteins can each increase genomic instability in virus-infected cells through multiple mechanisms. The working model of HPV-induced carcinogenic progression is that these events co-operate to enable immortalization and subsequent transformation of high-risk HPV-infected cells.

Fig 2

Proposed drivers of HPV carcinogenesis. (A) Mutation rates in growth-promoting signaling pathways in head and neck squamous cell carcinoma. Data from reference (24) were re-graphed to summarize somatic mutation rate data for genes in 10 different growth-promoting pathways in HPV-positive (HPV+) and HPV-negative (HPV−) HNSCC. Values indicate the percent of samples of each tumor type that have at least one genomic alteration in a signaling pathway. See reference (24) for more detail. (B) Conserved activities of high-risk HPV E7 oncoproteins. High-risk HPV oncoproteins bind and degrade pRB and, in a separate complex, recruit UBR4 to degrade PTPN14. High-risk HPV E6 proteins recruit the ubiquitin ligase E6AP to target p53 for proteasome-mediated degradation. Other host cell targets of HPV oncoproteins may contribute to cellular reprogramming that is required for virus replication, contribute to their carcinogenic activity, or both.