HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion.
TGF-β signaling can promote tumor formation and development or suppress it, depending on the cellular context and tumor stage. A potential target of this dual effect of TGF-β is HGF, as TGF-β can inhibit or promote its expression, although the mechanisms underlying this are largely unknown. In the present study, we found that mice with keratinocyte-specific deletion of the TGF-β signaling mediator Smad2 (referred to herein as K5.Smad2(-/-) mice), which have increased susceptibility to squamous cell carcinomas (SCCs), exhibited angiogenesis associated with epithelial overexpression of HGF and endothelial activation of the HGF receptor c-Met. Application of a c-Met inhibitor abrogated angiogenesis, suggesting that HGF overexpression plays a major role in angiogenesis associated with epithelial Smad2 loss. On the Hgf promoter, Smad2 was mainly associated with transcriptional corepressors, whereas Smad4 was mainly associated with the transcriptional coactivator CREB-binding protein (CBP/p300). Smad2 loss caused increased binding of Smad4 and CBP/p300 to the Hgf promoter. Consistent with this, knocking down Smad2 in human keratinocytes caused increased levels of HGF, which were abrogated by concomitant knockdown of Smad3 and Smad4. Importantly, the incidence of HGF-positive human SCC was high in cases with Smad2 loss and lower when Smad4 was also lost. We therefore conclude that Smad2 loss causes HGF upregulation via loss of Smad2-mediated transcriptional repression and enhanced Smad3/4-mediated transactivation. Since Smad2 is often downregulated in human SCCs, our data suggest a therapeutic strategy of blocking HGF/c-Met activation for Smad2-deficient SCCs.
Hoot
Kristina E
KE
Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA.
Oka
Masako
M
Han
Gangwen
G
Bottinger
Erwin
E
Zhang
Qinghong
Q
Wang
Xiao-Jing
XJ
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000209:etiology*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000502:physiology*; D051901:Smad4 Protein / Q000502:physiology; D015533:Transcriptional Activation
C066855:HGF protein, human; C553307:HGF protein, mouse; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051901:Smad4 Protein; D017228:Hepatocyte Growth Factor