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E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells

Oncogene volume 23, pages 350–358 (2004)Cite this article

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 α, β, and γ-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 β-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.

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Acknowledgements

We are grateful to Drs N Bachnou, D Hamilton, and M Loignon for critical reading of the manuscript. We also thank M Tong, C Serruya, and N Hamel for their technical assistance. This work was supported by the National Cancer Institute of Canada Grant # 010254 (WDF), the Canadian Genetic Diseases Network (WDF), the Fonds de la Recherche en Santé du Québec (FRSQ-Réseau du Cancer) (WDF, GB, LA, A-EA), and in part by Grant # 008491 and MT-14357 from the Canadian Breast Cancer Research Initiative and the Canadian Institutes for Health Research, respectively (MA-J).

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Author notes

  1. Ala-Eddin Al Moustafa: On behalf of the authors I (A-EA) dedicate this work to the memory of my beloved wife, Naima Bachnou.

Authors and Affiliations

  1. Departments of Medicine, Lady Davis Institute for Medical Research of the Sir Mortimer B. Davis-Jewish General Hospital, Oncology, Pathology, Pharmacology, and Therapeutics, and Center for Translational Research in Cancer, Quebec, Canada

    Ala-Eddin Al Moustafa, William D Foulkes, Naciba Benlimame, Annick Wong, Lily Yen, Josée Bergeron, Gerald Batist, Lesley Alpert & Moulay A Alaoui-Jamali

  2. Research Institute of the McGill University Health Centre, Quebec, Canada

    William D Foulkes

  3. Departments of Oncology and Human Genetics, Program in Cancer Genetics, McGill University, Montreal, Quebec, Canada

    Ala-Eddin Al Moustafa, William D Foulkes & Annick Wong

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  1. Ala-Eddin Al Moustafa
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Correspondence to William D Foulkes.

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Al Moustafa, AE., Foulkes, W., Benlimame, N. et al. E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. Oncogene 23, 350–358 (2004). https://doi.org/10.1038/sj.onc.1207148

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