High incidence of HPV-associated head and neck cancers in FA deficient mice is associated with E7's induction of DNA damage through its inactivation of pocket proteins

Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with 'high-risk' HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in F...

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Bibliographic Details
Published in:PloS one 2013-09, Vol.8 (9), p.e75056-e75056
Main Authors: Park, Jung Wook, Shin, Myeong-Kyun, Pitot, Henry C, Lambert, Paul F
Format: Article
Language:English
Subjects:
Anemia
Animals
Biomarkers, Tumor - metabolism
Cancer
Cell cycle
Cell growth
Cell Proliferation
Cervical cancer
Damage
Deactivation
Deoxyribonucleic acid
Disease susceptibility
DNA
DNA Damage
DNA repair
Epithelium - metabolism
Epithelium - pathology
Esophagus - metabolism
Esophagus - pathology
Fanconi Anemia Complementation Group D2 Protein - deficiency
Fanconi Anemia Complementation Group D2 Protein - metabolism
Fanconi syndrome
Fanconi's anemia
Genes
Genetic engineering
Head
Head & neck cancer
Head and neck
Head and Neck Neoplasms - pathology
Head and Neck Neoplasms - virology
Health risks
Histones - metabolism
Human papillomavirus
Inactivation
Incidence
Laboratories
Medical research
Medicine
Mice
Mice, Transgenic
Mutation
Neoplasm Proteins - metabolism
Oncogene Proteins, Viral - metabolism
Papillomavirus E7 Proteins - metabolism
Papillomavirus infections
Patients
Proteins
Public health
Repressor Proteins - metabolism
Risk factors
Rodents
Solid tumors
Studies
Tongue - metabolism
Tongue - pathology
Transgenic animals
Transgenic mice
Tumorigenesis
Tumors
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Summary:Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with 'high-risk' HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in FA patients is still unclear. We previously learned that FA deficiency in mice predisposes HPV16 E7 transgenic mice to HNCs. To address HPV16 E6's oncogenic potential under FA deficiency in HNCs, we utilized HPV16 E6-transgenic mice (K14E6) and HPV16 E6/E7-bi-transgenic mice (K14E6E7) on genetic backgrounds sufficient or deficient for one of the fanc genes, fancD2 and monitored their susceptibility to HNCs. K14E6 mice failed to develop tumor. However, E6 and fancD2-deficiency accelerated E7-driven tumor development in K14E6E7 mice. The increased tumor incidence was more correlated with E7-driven DNA damage than proliferation. We also found that deficiency of pocket proteins, pRb, p107, and p130 that are well-established targets of E7, could recapitulate E7's induction of DNA damage. Our findings support the hypothesis that E7 induces HPV-associated HNCs by promoting DNA damage through the inactivation of pocket proteins, which explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. Our results further demonstrate the unexpected finding that FA deficiency does not predispose E6 transgenic mice to HNCs, indicating a specificity in the synergy between FA deficiency and HPV oncogenes in causing HNCs.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0075056