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.

Copyright 2009 S. Karger AG, Basel.

Figures

Fig. 1

Schematic representation of the HPV life cycle in the context of a differentiating epithelium. Sections of normal uninfected (left) and HPV-infected epithelia (right) are represented in this illustration. The HPV life cycle is dependent on the differentiation program that keratinocytes undergo within a stratified epithelium. HPV virions infect dividing keratinocytes of the basal cell layer where they establish and maintain their genome as a low copy number episome in the nucleus of these cells. Although un-infected cells ultimately differentiate and lose their nuclei, expression of the viral oncogenes E6 and E7 prevents terminal differentiation of infected keratinocytes and keeps them in a proliferative state needed for viral DNA synthesis. As the cells migrate towards the upper layers of the epithelium, the viral genome is amplified and late gene expression is induced. Synthesis of the 2 capsid proteins allows for the viral DNA to be packaged into mature virions, which are then released from the top portion of the epithelium through natural shedding. The different cell layers of the epithelium and the viral events occurring within them are indicated on the left and right side of the figure, respectively.

Fig. 2

Schematic representation of the HPV oncoproteins E6 and E7. a E7 harbours 1 zinc finger (Zn) in its C-terminal domain and 2 amino-terminal conserved regions. Conserved region 2 contains the consensus sequence LxCxE required for pRb binding, and is highly conserved among HPV types, as well as in adenovirus type 5 E1A protein (Ad5 E1A) and simian virus 40 large T antigen (SV40 large T). b E6 harbours 2 zinc finger domains. A C-terminal PDZ-binding domain of the consensus sequence x-(T/S)-x-(V/L) is also present in the E6 proteins from high-risk HPV types (HPVs 16 and 18), but is absent in their low-risk counterparts (HPVs 6 and 11).

Fig. 3

Molecular mechanisms of HPV-induced cellular proliferation and genomic instability. HPV E7 induces cellular proliferation by 4 main mechanisms that culminate in the activation of E2F and re-entry of cells into S-phase. These mechanisms involve: (1) inhibition and degradation of pRb and related pocket proteins p107 and p130; (2) stimulation of cyclinA/E-Cdk2 synthesis and activity; (3) inhibition of the Cdk2 inhibitors p21 and p27; (4) inhibition of specific histone deacetylases (HDAC) involved in E2F repression. E6 also contributes to cellular proliferation through its inhibition of p53, which results in decreased transcription of p21 and p27 and prevention of E7-induced apoptosis. These synergistic effects of E6 and E7 result in uncontrolled cell division and high genomic instability, possibly facilitating viral integration into the host genome. Integration events that disrupt the E2 open reading frame lead to an increase in E6 and E7 expression and associated genomic instability, a hallmark of cancerous cells.

Fig. 4

Cellular proteins and processes affected by the HPV E6 oncoprotein. E6 interacts with several cellular proteins involved in apoptosis, tissue integrity, telomerase regulation and IFN antiviral response. The primary anti-apoptotic function of E6 is to inhibit p53. E6 also interferes with other cellular proteins involved in intrinsic and extrinsic apoptotic pathways, including Bax, Bak and downstream effectors of death receptor signalling. Additionally, E6 contributes to the disruption of tissue integrity by binding to focal adhesion molecules and PDZ domain-containing proteins. E6 also helps HPV-induced cellular immortalization by its induction of the telomerase hTERT proceeding through transcriptional activation by Myc and Sp1, as well as by inhibition of the transcriptional repressor NFX1-91. Finally, E6 also inhibits the host IFN antiviral response.