Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo.
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.
DiVito
Kyle A
KA
Department of Biochemistry & Molecular Biology, Georgetown University School of Medicine Washington, DC, USA.
Trabosh
Valerie A
VA
Chen
You-Shin
YS
Chen
Yu
Y
Albanese
Chris
C
Javelaud
Delphine
D
Mauviel
Alain
A
Simbulan-Rosenthal
Cynthia M
CM
Rosenthal
Dean S
DS
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
D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D051176:beta Catenin; D049452:Green Fluorescent Proteins