Published online before print April 1, 2008

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(American Journal of Pathology. 2008;172:1391-1402.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071004

Transforming Growth Factor-β1-Mediated Slug and Snail Transcription Factor Up-Regulation Reduces the Density of Langerhans Cells in Epithelial Metaplasia by Affecting E-Cadherin Expression

Michael Herfs^*, Pascale Hubert^*, Natalia Kholod^*, Jean Hubert Caberg^*, Christine Gilles, Geert Berx, Pierre Savagner, Jacques Boniver^* and Philippe Delvenne^*

From the Department of Pathology^* and the Laboratory of Tumour and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Cancer), University of Liege, Liege, Belgium; the Department for Molecular Biomedical Research, Unit of Molecular and Cellular Oncology, Ghent University, Ghent, Belgium; and the Centre de Recherche en Cancerologie, Centre Régional de Lutte contre le Cancer, Val d’Aurelle-Paul Lamarque, Montpellier, France

Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a⁺ LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-β1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-β1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis.