HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion

Abstract

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.

Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis

“…Thus, Smad7 binding to SBE appears necessary to expel signaling Smads to abrogate Rac1 repression. Among known Smad transcriptional co-repressors 29–31 , we found that CtBP1 bound to the Rac1 promoter SBE-1.5 Kb site in wildtype keratinocytes (Fig. 3g), and Smad7 transgene expression significantly reduced CtBP1 binding to the SBE (Fig.…”

Targeting the vascular and perivascular niches as a regenerative therapy for lung and liver fibrosis

“…Loss of these pathways might not only impair regeneration but also cause fibrosis. It was shown before that activation of Smad2/3 blocks HGF transcription in keratinocytes (99). Whether the TGF/Smad pathway mediates the subversion of epithelially-inductive vascular niche function during parenchymal repair can be explored in the future.…”

Selective improvement in renal function preserved remote myocardial microvascular integrity and architecture in experimental renovascular disease

“…Microvascular rarefaction is frequently found in hypertension and ARVD, but was prevented in ARVD + EPC, and might have improved microvascular availability. Restoration of microvascular density could be related to decreased ischemic episodes, downregulation of TGF-β [42], and amelioration of myocardial fibrosis, which in turn facilitates microvascular network development.…”