title: Transforming growth factor-beta1-mediated Slug and Snail transcription factor up-regulation reduces the density of Langerhans cells in epithelial metaplasia by affecting E-cadherin expression.
abstract: 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-beta1 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-beta1 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.
authors.affiliation: Department of Pathology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Cancer), University of Liege, 4000 Liege, Belgium. m.herfs@student.ulg.ac.be
authors.forename: Michael
authors.initials: M
authors.lastname: Herfs
authors.forename: Pascale
authors.initials: P
authors.lastname: Hubert
authors.forename: Natalia
authors.initials: N
authors.lastname: Kholod
authors.forename: Jean Hubert
authors.initials: JH
authors.lastname: Caberg
authors.forename: Christine
authors.initials: C
authors.lastname: Gilles
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
authors.forename: Pierre
authors.initials: P
authors.lastname: Savagner
authors.forename: Jacques
authors.initials: J
authors.lastname: Boniver
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
mesh_terms: D000328:Adult; D015703:Antigens, CD; D018949:Antigens, CD1 / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology*; D019175:DNA Methylation; D004848:Epithelium / Q000473:pathology; D005260:Female; D020868:Gene Silencing; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D007801:Langerhans Cells / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D018949:Antigens, CD1; C513384:CDH1 protein, human; D015820:Cadherins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1