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1.
Virology ; 554: 9-16, 2021 02.
Article in English | MEDLINE | ID: mdl-33321328

ABSTRACT

HPV-inactive head and neck and cervical cancers contain HPV DNA but do not express HPV E6/E7. HPV-positive primary head and neck tumors usually express E6/E7, however they may produce HPV-inactive metastases. These observations led to our hypothesis that HPV-inactive cancers begin as HPV-active lesions, losing dependence on E6/E7 expression during progression. Because HPV-inactive cervical cancers often have mutated p53, we investigated whether p53 loss may play a role in the genesis of HPV-inactive cancers. p53 knockout (p53-KO) by CRISPR-Cas9 resulted in a 5-fold reduction of E7 mRNA in differentiation-resistant HPV16 immortalized human keratinocytes (HKc/DR). E7 expression was restored by 5-Aza-2 deoxycytidine in p53 KO lines, suggesting a role of DNA methylation in this process. In-situ hybridization showed that p53 KO lines consist of mixed populations of E6/E7-positive and negative cells. Hence, loss of p53 predisposes HPV16 transformed cells to losing dependence on the continuous expression of HPV oncogenes for proliferation.


Subject(s)
Cell Transformation, Viral , Human papillomavirus 16/physiology , Keratinocytes/physiology , Keratinocytes/virology , Oncogene Proteins, Viral/genetics , Papillomavirus E7 Proteins/genetics , Repressor Proteins/genetics , Tumor Suppressor Protein p53/genetics , CRISPR-Cas Systems , Cell Line, Transformed , Cell Proliferation , Cell Survival , Gene Expression , Gene Knockout Techniques , Genes, p53 , Human papillomavirus 16/genetics , Humans , Loss of Function Mutation , Oncogene Proteins, Viral/metabolism , Papillomavirus E7 Proteins/metabolism , Repressor Proteins/metabolism , Transfection , Tumor Suppressor Protein p53/physiology
2.
Clin Transl Med ; 3(1): 60, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25632320

ABSTRACT

Positive markers of epithelial-mesenchymal transition (EMT) in head and neck cancers complicate clinical management and are associated with reduced survival. We discuss recent translational discoveries in EMT and suggest additional actionable molecular pathways, biomarkers, and clinical agents.

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