title: Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo.
abstract: The list of transforming growth factor-beta (TGF-β)-related proteins in non-canonical TGF-β signaling is growing. Examples include receptor-Smads directing micro-RNA processing and inhibitory-Smads, e.g. Smad7, directing cell adhesion. Human skin grafts with fluorescently tagged melanoma cells revealed Smad7-expressing cells positioned themselves proximal to the dermal-epidermal junction and failed to form tumors, while control cells readily invaded and formed tumors within the dermis. Smad7 significantly inhibited β-catenin T41/S45 phosphorylation associated with degradation and induced a 4.5-fold increase in full-length N-cadherin. Cell adhesion assays confirmed a strong interaction between Smad7-expressing cells and primary dermal fibroblasts mediated via N-cadherin, while control cells were incapable of such interaction. Immunofluorescent analysis of skin grafts indicated N-cadherin homotypic interaction at the surface of both Smad7 cells and primary dermal fibroblasts, in contrast to control melanoma cells. We propose that Smad7 suppresses β-catenin degradation and promotes interaction with N-cadherin, stabilizing association with neighboring dermal fibroblasts, thus mitigating invasion.
authors.affiliation: Department of Biochemistry & Molecular Biology, Georgetown University School of Medicine Washington, DC, USA.
authors.forename: Kyle A
authors.initials: KA
authors.lastname: DiVito
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Trabosh
authors.forename: You-Shin
authors.initials: YS
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Delphine
authors.initials: D
authors.lastname: Javelaud
authors.forename: Alain
authors.initials: A
authors.lastname: Mauviel
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Simbulan-Rosenthal
authors.forename: Dean S
authors.initials: DS
authors.lastname: Rosenthal
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002450:Cell Communication; D045744:Cell Line, Tumor; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016038:Skin Transplantation; D051906:Smad7 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D051176:beta Catenin; D049452:Green Fluorescent Proteins