Abstract
The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Carcinogenesis / drug effects
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Carcinogenesis / genetics*
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Cell Line, Tumor
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Cell Proliferation / genetics
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Datasets as Topic
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Disease Models, Animal
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Disease-Free Survival
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Viral / drug effects
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Host-Pathogen Interactions / genetics
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Human papillomavirus 16 / genetics
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Human papillomavirus 16 / pathogenicity
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Humans
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Mice
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Mice, Transgenic
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Oncogene Proteins, Viral / genetics*
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Papillomavirus Infections / drug therapy
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Papillomavirus Infections / genetics*
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Papillomavirus Infections / mortality
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Papillomavirus Infections / virology
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Pharyngeal Neoplasms / drug therapy
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Pharyngeal Neoplasms / genetics*
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Pharyngeal Neoplasms / mortality
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Pharyngeal Neoplasms / virology
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Primary Cell Culture
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors
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Receptors, Fibroblast Growth Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Squamous Cell Carcinoma of Head and Neck / drug therapy
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Squamous Cell Carcinoma of Head and Neck / genetics*
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Squamous Cell Carcinoma of Head and Neck / pathology
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Squamous Cell Carcinoma of Head and Neck / virology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / metabolism
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Tumor Suppressor Protein p53 / metabolism
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Uterine Cervical Neoplasms / drug therapy
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Uterine Cervical Neoplasms / genetics*
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Uterine Cervical Neoplasms / mortality
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Uterine Cervical Neoplasms / virology
Substances
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Oncogene Proteins, Viral
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Receptors, Fibroblast Growth Factor
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TP53 protein, human
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Tumor Suppressor Protein p53
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MTOR protein, human
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TOR Serine-Threonine Kinases