The molecular mechanism of human papillomavirus-induced carcinogenesis in head and neck squamous cell carcinoma

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Recently, the incidence of oropharyngeal cancer (OPC) has increased markedly in comparison to that of HNSCC, which is associated with the use of tobacco or alcohol or both. This increase has resulted mainly from the global rise in the number of human papillomavirus (HPV)-related oropharyngeal cancers (HPV-OPCs). HPV-OPC has several unique characteristics, including presentation in younger patients, better response rates to treatment, and better prognosis compared to alcohol- and smoking-related HNSCC. HPV infection status is now an independent prognostic factor for survival in patients with OPC. In general, HPV oncoproteins E6 and E7 are the primary viral factors responsible for the initiation and progression of HPV-related cancers via the inactivation of p53 and pRb. However, alterations in additional factors, including genomic instability, HPV DNA integration, and epigenetic alterations, could be equally important for neoplastic transformation and tumor progression. The impact of genomic instability and external environmental factors on the initiation of cervical cancer development through high-risk HPV infection has been well characterized, although less is known about the mechanism underlying HPV-induced carcinogenesis in HNSCC. This review provides an overview of the biology and molecular mechanisms of HPV-related cancers, including a particular focus on several recent studies on the comprehensive characterization of genomic alterations in HPV-associated HNSCC.

Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV‐associated head and neck squamous cell carcinoma cell lines

“…High-risk HPV infection of mucosal epithelia leads to the expression of viral E6 and E7 oncoproteins inducing the inactivation of both the p53 and the retinoblastoma (Rb) tumor suppressive proteins, which contribute to the malignant formation of HPV-related cancers. In addition, immune escape, genomic instability, HPV DNA integration, and epigenetic alterations are also important for HPV-related cancer progression 6 . In fact, high-risk HPV integration is now known to be associated with the progression from low- to high-grade cervical intraepithelial neoplasia 7 .…”

“…In addition, immune escape, genomic instability, HPV DNA integration and epigenetic alterations are also important for HPV-related cancer progression. 6 In fact, highrisk HPV integration is now known to be associated with the progression from low-to high-grade cervical intraepithelial neoplasia. 7 Many epigenetic alterations have also been reported during the process of cervical carcinogenesis in both the HPV and human genomes.…”

Comparison of detection methods for HPV status as a prognostic marker for loco-regional control after radiochemotherapy in patients with HNSCC

“…In turn, E2 transcription factors are activated resulting in expression of S-phase-related genes and thus cell cycle progression [19]. This functional inactivation of the Rb-pathway finally leads to p16 over-expression -a phenomenon which is commonly used as surrogate marker for HPV infection in HNSCC (reviewed in [20]). In addition, the HPV E6 oncoprotein initiates ubiquitylation and subsequent proteasomal degradation of p53, impaired activation of p21, and finally uncontrolled cell cycle progression.…”

“…In addition, the HPV E6 oncoprotein initiates ubiquitylation and subsequent proteasomal degradation of p53, impaired activation of p21, and finally uncontrolled cell cycle progression. Accordingly, it is of similar relevance for HNSCC pathogenesis as HPV E7 [20,21], and detection of HPV E6 and/or E7 is frequently used for diagnostic purposes [22].…”

Inhibition of nonsense-mediated decay rescues functional p53β/γ isoforms in MDM2-amplified cancers

“…HPV-associated cancers include cervical, head and neck, vulval, vaginal, penile and anal cancers (Table EV3). The major cause of pathogenesis 7 in cancers induced by HPV infection is the p53 deficiency arising from its E6 oncoviral proteinmediated degradation, even though p53 is predominantly WT (Scheffner, Werness et al 1990, Balz, Scheckenbach et al 2003, Strati and Lambert 2008, Sano and Oridate 2016, Faraji, Zaidi et al 2017. The amino acid residues 94-292 in p53 comprise the core binding region for E6mediated degradation Coffino 1996, Martinez-Zapien, Ruiz et al 2016) and though p53β/ isoforms retain this region, lack of the C-terminus may alter the tertiary structure of the E6/E6AP/p53/ complex, impeding their degradation.…”