title: E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells.
abstract: Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and spread to cervical lymph nodes, with distant metastases developing in 30-40% of cases. HPV-16 is an important risk factor for HNSCC. How HPV enhances susceptibility to HNSCC is not fully understood, but seems to involve cofactors. In this study, we examined the effect of the cooperation between HPV-16 and the tyrosine kinase receptor ErbB-2 on E-cadherin/catenin complex patterns and neoplastic transformation of human normal oral epithelial (NOE) cells. We report that overexpression of ErbB-2 or E6/E7 alone does not affect E-cadherin/catenin complex patterns nor does it induce cell transformation of NOE cells. In contrast, coexpression of E6/E7 and ErbB-2 downregulates E-cadherin and catenin expression. This is accompanied by cytoplasmic localization of E-cadherin, as well as nuclear translocation of alpha, beta, and gamma-catenins. Furthermore, we demonstrate that E6/E7 cooperate with overexpressed ErbB-2 to induce tumor formation in nude mice and to upregulate cyclin D1 and c-myc expression. Our data suggest that E6/E7 cooperate with ErbB-2 in head and neck carcinogenesis, at least in part, via the conversion of beta-catenin from a cell adhesion to a nuclear function, that is, to act as a potential transcriptional regulator. This conversion leads to the upregulation of cyclin D1, c-myc and other oncoproteins necessary for alteration of the E-cadherin/catenin complex and cell transformation of NOE cells.
authors.affiliation: Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital, Department of Medicine, and Center for Translational Research in Cancer, Quebec, Canada.
authors.forename: Ala-Eddin
authors.initials: AE
authors.lastname: Al Moustafa
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Naciba
authors.initials: N
authors.lastname: Benlimame
authors.forename: Annick
authors.initials: A
authors.lastname: Wong
authors.forename: Lily
authors.initials: L
authors.lastname: Yen
authors.forename: Josée
authors.initials: J
authors.lastname: Bergeron
authors.forename: Gerald
authors.initials: G
authors.lastname: Batist
authors.forename: Lesley
authors.initials: L
authors.lastname: Alpert
authors.forename: Moulay A
authors.initials: MA
authors.lastname: Alaoui-Jamali
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D005881:Gingiva / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D010160:Palate, Soft / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D027383:Papillomaviridae / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D015820:Cadherins; D019938:Cyclin D1; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C068651:E6 protein, Human papillomavirus type 16; C059731:oncogene protein E7, Human papillomavirus type 16