Keratinocyte-specific Smad2 ablation results in increased epithelial-mesenchymal transition during skin cancer formation and progression.
TGF-beta and its signaling mediators, Smad2, -3, and -4, are involved with tumor suppression and promotion functions. Smad4-/- mouse epidermis develops spontaneous skin squamous cell carcinomas (SCCs), and Smad3-/- mice are resistant to carcinogen-induced skin cancer; however, the role of Smad2 in skin carcinogenesis has not been explored. In the present study, we found that Smad2 and Smad4, but not Smad3, were frequently lost in human SCCs. Mice with keratinocyte-specific Smad2 deletion exhibited accelerated formation and malignant progression of chemically induced skin tumors compared with WT mice. Consistent with the loss of Smad2 in poorly differentiated human SCCs, Smad2-/- tumors were poorly differentiated and underwent epithelial-mesenchymal transition (EMT) prior to spontaneous Smad4 loss. Reduced E-cadherin and activation of its transcriptional repressor Snail were also found in Smad2-/- mouse epidermis and occurred more frequently in Smad2-negative human SCCs than in Smad2-positive SCCs. Knocking down Snail abrogated Smad2 loss-associated EMT, suggesting that Snail upregulation is a major mediator of Smad2 loss-associated EMT. Furthermore, Smad2 loss led to a significant increase in Smad4 binding to the Snail promoter, and knocking down either Smad3 or Smad4 in keratinocytes abrogated Smad2 loss-associated Snail overexpression. Our data suggest that enhanced Smad3/Smad4-mediated Snail transcription contributed to Smad2 loss-associated EMT during skin carcinogenesis.
Hoot
Kristina E
KE
Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, Oregon 97239-2999, USA.
Lighthall
Jessyka
J
Han
Gangwen
G
Lu
Shi-Long
SL
Li
Allen
A
Ju
Wenjun
W
Kulesz-Martin
Molly
M
Bottinger
Erwin
E
Wang
Xiao-Jing
XJ
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D002478:Cells, Cultured; D018450:Disease Progression; D004848:Epithelium / Q000473:pathology; D019085:Fluorescent Antibody Technique, Direct; D017353:Gene Deletion; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000378:metabolism; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D051899:Smad2 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse