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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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4-Nitroquinoline-1-oxide / metabolism
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Animals
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Biomarkers, Tumor / metabolism*
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Carcinogens / metabolism
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Carcinoma, Squamous Cell / pathology
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Carcinoma, Squamous Cell / virology*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Proliferation
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Epithelial Cells / cytology
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Epithelial Cells / physiology
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Esophagus / anatomy & histology
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Head and Neck Neoplasms / pathology
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Head and Neck Neoplasms / virology*
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Human papillomavirus 16 / metabolism*
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Humans
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Mice
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Mice, Transgenic
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Minichromosome Maintenance Complex Component 7
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Mouth Mucosa / cytology
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Neoplasm Metastasis
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oncogene Proteins, Viral / genetics
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Papillomavirus E7 Proteins
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Repressor Proteins / genetics
Substances
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Biomarkers, Tumor
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Carcinogens
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins
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E6 protein, Human papillomavirus type 16
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Nuclear Proteins
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Oncogene Proteins, Viral
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Papillomavirus E7 Proteins
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Repressor Proteins
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oncogene protein E7, Human papillomavirus type 16
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4-Nitroquinoline-1-oxide
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Mcm7 protein, mouse
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Minichromosome Maintenance Complex Component 7