Files
Abstract
Smad2 and Smad4, but not Smad3, are frequently lost in human skin squamous cell carcinomas (SCCs. Keratinocyte‑specific Smad2 knockout mice showed accelerated tumor formation, poor differentiation, and epithelial–mesenchymal transition (EMT), driven by increased Snail expression. Smad2 loss enhanced Smad3/Smad4‑mediated Snail transcription. Both Smad2‑ and Smad4‑deficient tumors exhibited increased angiogenesis, but through distinct pathways: Smad4 loss elevated VEGF and TGFβ‑dependent signaling, whereas Smad2 loss increased hepatocyte growth factor (HGF). Promoter studies showed Smad2 normally represses HGF while Smad4 activates it. Overall, Smad2 and Smad4 deletions promote EMT and angiogenesis through complementary mechanisms that drive skin carcinogenesis.