Identification of biomarkers that distinguish human papillomavirus (HPV)-positive versus HPV-negative head and neck cancers in a mouse model

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer mortality worldwide. Recent reports have associated a subset of HNSCC with high-risk human papillomaviruses (HPVs), particularly HPV16, the same subset of HPVs responsible for the majority of cervical and anogenital cancers. In this study we describe a mouse model for HPV-associated HNSCC that employs mice transgenic for the HPV16 oncogenes E6 and E7. In these mice, E6 and E7 induce aberrant epithelial proliferation and, in the presence of a chemical carcinogen, they increase dramatically the animal's susceptibility to HNSCC. The cancers arising in the HPV16-transgenic mice mirror the molecular and histopathological characteristics of human HPV-positive HNSCC that distinguish the latter from human HPV-negative HNSCC, including overexpression of p16 protein and formation of more basaloid cancers. This validated model of HPV-associated HNSCC provides the means to define the contributions of individual HPV oncogenes to HNSCC and to understand the molecular basis for the differing clinical properties of HPV-positive and HPV-negative human HNSCC. From this study, we identify minichromosome maintenance protein 7 (MCM7) and p16 as potentially useful biomarkers for HPV-positive head and neck cancer.head and neck squamous cell carcinoma (HNSCC) ͉ human papillomavirus 16 (HPV16) ͉ minichromosome maintenance protein 7 (MCM7) ͉ p16 ͉ transgenic H ead and neck cancers are the sixth most common malignancy in the world (1), and recent advances in treating them are not reflected in improved survival. Head and neck squamous cell carcinoma (HNSCC) is etiologically associated with tobacco use; alcohol consumption; and, in Southeast Asia, chewing of betel nut (2-6). However, more recent studies have implicated high-risk human papillomaviruses (HR-HPVs), the same viruses recognized as the causative agents of cervical and most other anogenital malignancies, in the etiology of a subset of HNSCC (7).HR-HPV DNA has been detected in Ϸ20% of HNSCC, particularly in malignancies of the oropharynx, where Ϸ50% of the cancers have been found to harbor viral DNA. HPV16, the type associated with the majority of cervical carcinomas, is the HR-HPV linked with the overwhelming majority of HPVpositive HNSCC (95%) (8-10). Other HR-HPV genotypes have been detected, including HPV18, HPV31, and HPV33. Viral oncogenes E6 and E7, the papillomaviral genes considered largely responsible for the onset as well as persistence of cervical cancer, have been detected in both integrated and extrachromosomal HPV genomes in HNSCC (11). E6 and E7 are best known for their ability to bind and inactivate the tumor suppressors p53 and pRb (12)(13)(14)(15)(16)(17), and these respective properties have been associated with their oncogenic properties (18,19). Consistent with E6 and E7 contributing to HPV-positive HNSCC is the absence of genetic or epigenetic alterations in the p53 and pRb pathways in HPV-positive HNSCC, in stark contrast to what is observed in HPV-negative HNSCC (11). Furthermore, di...

Biology of Human Papillomavirus Infections in Head and Neck Carcinogenesis

“…The HPV types have also been grouped into mucosal or cutaneous types, based on their tropism for specific epithelial sites. Mucosal HPV types found preferentially in precancerous and cancerous lesions have been designated as 'high-risk' types and these include types 16,18,31,33,34,35,39,45,51,52,56,58,59, 66, 68, and 70. Mucosal HPVs found in benign genital warts and other non-malignant lesions are generally labeled as 'low-risk' types, the most important ones being HPV 6,11,42,43, and 44 [1,2].…”

“…In this model, K14E6 and K14E7 mice were crossed but E6 and E7 could only induce a suprabasal DNA synthesis in the oral cavity [49,50]. On the contrary, when the mice were treated with the oral carcinogen 4-nitroquinoline-noxide (4-NQO) in their drinking water as a co-carcinogen, the animals were dramatically more susceptible to carcinogenesis and developed tumors almost fully penetrant as compared to the low tumor incidence in the like-treated non-transgenic control group [51]. Subsequently, the same group showed that E7 is the dominant HPV oncoprotein in HNSCC, and they also reported that pRb/p107-deficient mice developed HNSCC as frequently as did HPV-16 E7 transgenic mice.…”

Adenosquamous Carcinoma of the Head and Neck: Relationship to Human Papillomavirus and Review of the Literature

“…It is overexpressed in HPV-related SCC but is usually deleted or otherwise inactivated in non-HPV-related head and neck SCC [19,20]. p16 expression by immunohistochemistry approaches 100% in HPVpositive oropharyngeal carcinomas in some studies [5,11,21,22] and is indicative of transcriptionally-active HPV.…”

Subpath analysis of each subtype of head and neck cancer based on the regulatory relationship between miRNAs and biological pathways

“…MCM2 (a member of MCM family) expression is found to be aberrant in laryngeal squamous epithelial lesions (54). In addition, MCM7 is identified as a useful biomarker for HPV-positive HNSCC (55). Our data indicate that miR-519A may act as a therapeutic biomarker for HNSCC by targeting the DNA replication associated protein MCM7.…”