Molecular mechanisms of human papillomavirus-related carcinogenesis in head and neck cancer

Abstract

This review examines the general cellular and molecular underpinnings of human papillomavirus (HPV)-related carcinogenesis in the context of head and neck squamous cell carcinoma (HNSCC) and focuses on HPV-positive oropharyngeal squamous cell carcinoma in areas for which specific data is available. It covers the major pathways dysregulated in HPV-positive HNSCC and the genome-wide changes associated with this disease.

Keywords: Chromatin; HNSCC; HPV; Oropharyngeal; Squamous cell carcinoma; Viral integration.

Figure 1. The HPV16 genome

Schematic of HPV16 genome designed from Ref Seq entry: NC_001526. Viral genes E6 and E7 are marked in light red; E1, E2, E4, E5 in purple; and L1 and L2 in blue. Green regions marked E1, E2 are binding sites for the corresponding proteins. LCR: long control region; TSS_E: transcription start site for viral early genes; TSS_L: transcription start site for viral late genes; TATA in red represents the TATA box transcription factor binding site. SP1 represents the binding site for the host SP1 transcription factor. Although numerical base markers represent viral genomic positions, the coding elements are not to scale.

Figure 2. Tumor progression model for HPV-related carcinogenesis

(A) In the head and neck, HPV demonstrates tropism for lymphoid-associated structure of the oropharynx, including the palatine and lingual tonsils (area in black box). (B) In the oropharynx, HPV gains access to basal keratinocyte progenitors through fenestrations in the reticulated epithelium of the tonsillar crypts. (C) Infection of the tonsillar epithelium result aberrant basal cell differentiation, dysplasia, carcinoma in situ, and finally invasive carcinoma. (D) Hypothetical model for somatic mutations in a multistage tumor progression model. Genes and loci in red are upregulated or activated or show increase in copy number. Genes in green undergo loss of function mutation or deletion. CNV, copy number variations.

Figure 3. Cell cycle perturbation by human papillomavirus

(A) Schematic representing physiologic cell cycle regulation. Tumor suppressor proteins are marked blue, proto-oncoproteins are marked red. The CDKN2A gene encodes p14^ARF and p16^INK4A proteins. p14^ARF inhibits MDM2, thereby disinhibiting p53 to activate p21 and stop progression through the G2/M checkpoint into mitosis. p16^INK4A inhibits the CyclinD1/CDK4 and CyclinD1/CDK6 complexes. These complexes catalyze phosphorylation of the retinoblastoma protein (Rb), inducing it to release E2F family transcription factors to enter the nucleus and activate transcription of S-phase promoting transcripts. Phosphorylation of Rb also results in feedback inhibition of p16^INK4A expression. (B) HPV E6 oncoprotein binds and targets p53 for degradation, resulting in loss of G2/M checkpoint regulation. HPV E7 oncoprotein binds and targets Rb for degradation, resulting in the nuclear translocation of E2F and promotion of S-phase transition. In addition, downregulation of Rb results loss of feedback inhibition and overexpression of p16^INK4A.

Figure 4. Model for HPV integration promoting tumorigenesis

(A) Breakpoints in the viral genome often occur in the E2 gene. (B) Through interruption of the E2 gene, viral linearization leads to unregulated expression of E6 and E7 viral oncogenes, represented by the bold arrow at TSS_E. (C) The linearized viral genome inserts into a segment of open chromatin. Although this schematic shows viral DNA integrating at an enhancer, it may also integrate at genic or other transcriptionally active loci. (D) Viral DNA integration may result in the disruption in the expression of nearby genes. In a simplified example depicted here, integration of the viral genome upstream of a host tumor suppressor gene results in its transcriptional inhibition. However, viral integration into gene introns has also been demonstrated gene alter gene expression and alternative splicing.