HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific
Smad2 deletion.
Authors Hoot KE, Oka M, Han G, Bottinger E, Zhang Q, Wang XJ
Submitted By Submitted Externally on 6/9/2015
Status Published
Journal The Journal of clinical investigation
Year 2010
Date Published 10/1/2010
Volume : Pages 120 : 3606 - 3616
PubMed Reference 20852387
Abstract TGF-ß 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-ß is HGF, as TGF-ß 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-ß
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.

Investigators with authorship
Erwin BottingerMount Sinai School of Medicine