Human papillomavirus type 16 E6 and E7 oncoproteins act synergistically to cause head and neck cancer in mice

Abstract

High-risk human papillomaviruses (HPVs) contribute to cervical and other anogenital cancers, and they are also linked etiologically to a subset of head and neck squamous cell carcinomas (HNSCC). We previously established a model for HPV-associated HNSCC in which we treated transgenic mice expressing the papillomaviral oncoproteins with the chemical carcinogen 4-nitroquinoline-1-oxide (4-NQO). We found that the HPV-16 E7 oncoprotein was highly potent in causing HNSCC, and its dominance masked any potential oncogenic contribution of E6, a second papillomaviral oncoprotein commonly expressed in human cancers. In the current study, we shortened the duration of treatment with 4-NQO to reduce the incidence of cancers and discovered a striking synergy between E6 and E7 in causing HNSCC. Comparing the oncogenic properties of wild-type versus mutant E6 genes in this model for HNSCC uncovered a role for some but not other cellular targets of E6 previously shown to contribute to cervical cancer.

Human Papillomavirus Infections: Warts or Cancer?

“…Long-term exposure to estrogen is required. These studies have verified the importance of destabilization of pRB, TP53, and PDZ domain proteins in cancer development (Chung et al 2010;Jabbar et al 2010;Maufort et al 2010;Stelzer et al 2010, and references therein).…”

HPV-16/18 detection does not affect the prognosis of head and neck squamous cell carcinoma in younger and older patients

“…The role of high-risk HPV in HNSCC has recently been highlighted in the oropharynx (13), oral cavity (14), larynx (15), hypopharynx (11,12) and in HNSCC metastasis (17). The relevance of the high-risk HPV-E6/E7 protein for the carcinogenesis of multiple head and neck sites was demonstrated in transgenic mice (28)(29)(30). In addition, there is no consensus in the literature to detect HPV infection (20).…”

Biology of Human Papillomavirus Infections in Head and Neck Carcinogenesis

“…Seven years later, in 1983, we published the first evidence suggesting that a subgroup (some 20 %) of oral cancers is associated with HPV, based on detection of HPV structural proteins in these lesions using an antibody prepared against pooled HPV types [39]. We subsequently identified HPV types 11, 16 and 18 in these samples [40][41][42][43][44][45][46][47][48][49]. This concept has now been well accepted, and a growing body of evidence is supporting that approximately 20 % of oral cancers and 60-80 % of oropharyngeal cancers are caused by HPV [41][42][43][44].…”

“…This is supported by a bi-transgenic mouse model of HPV-associated HNSCC, developed by Lambert and coworkers. 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. Thus, inactivation of these two pocket proteins by E7 primarily drives E7 oncogenic properties in HPV-positive HNSCC [49]. The HPV copy numbers found in HNSCCs are often lower than detected in cervical cancers.…”