title: Dioxin receptor expression inhibits basal and transforming growth factor β-induced epithelial-to-mesenchymal transition.
abstract: Recent studies have emphasized the role of the dioxin receptor (AhR) in maintaining cell morphology, adhesion, and migration. These novel AhR functions depend on the cell phenotype, and although AhR expression maintains mesenchymal fibroblasts migration, it inhibits keratinocytes motility. These observations prompted us to investigate whether AhR modulates the epithelial-to-mesenchymal transition (EMT). For this, we have used primary AhR(+/+) and AhR(-/-) keratinocytes and NMuMG cells engineered to knock down AhR levels (sh-AhR) or to express a constitutively active receptor (CA-AhR). Both AhR(-/-) keratinocytes and sh-AhR NMuMG cells had increased migration, reduced levels of epithelial markers E-cadherin and β-catenin, and increased expression of mesenchymal markers Snail, Slug/Snai2, vimentin, fibronectin, and α-smooth muscle actin. Consistently, AhR(+/+) and CA-AhR NMuMG cells had reduced migration and enhanced expression of epithelial markers. AhR activation by the agonist FICZ (6-formylindolo[3,2-b]carbazole) inhibited NMuMG migration, whereas the antagonist α-naphthoflavone induced migration as did AhR knockdown. Exogenous TGFβ exacerbated the promigratory mesenchymal phenotype in both AhR-expressing and AhR-depleted cells, although the effects on the latter were more pronounced. Rescuing AhR expression in sh-AhR cells reduced Snail and Slug/Snai2 levels and cell migration and restored E-cadherin levels. Interference of AhR in human HaCaT cells further supported its role in EMT. Interestingly, co-immunoprecipitation and immunofluorescence assays showed that AhR associates in common protein complexes with E-cadherin and β-catenin, suggesting the implication of AhR in cell-cell adhesion. Thus, basal or TGFβ-induced AhR down-modulation could be relevant in the acquisition of a motile EMT phenotype in both normal and transformed epithelial cells.
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain.
authors: Eva M
authors: EM
authors: Rico-Leo
authors: Servicio de Técnicas Aplicadas a las Biociencias, Universidad de Extremadura, 06071 Badajoz, Spain.
authors: Alberto
authors: A
authors: Alvarez-Barrientos
authors: Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain. Electronic address: pmfersal@unex.es.
authors: Pedro M
authors: PM
authors: Fernandez-Salguero
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002465:Cell Movement; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006706:Homeostasis; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence / Q000379:methods; D034622:RNA Interference; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis* / Q000235:genetics; D012190:Retroviridae; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D016212:Transforming Growth Factor beta
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