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

Hoot, Kristina E.; Oka, Masako; Han, Gangwen; Böttinger, Erwin P.; Zhang, Qinghong; Wang, Xiaojing

doi:10.1172/jci69077

Cited by 15 publications

(24 citation statements)

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“…[18][19][20] As for the expression of Npnt, Tsukasaki et al reported its suppression by Smad2, 21) while the present findings demonstrated its activation by Smad4. Together, these observations led us to speculate that the Npnt expression is also regulated by a transcription co-activator protein such as CBP/p300, and mediated by the competition between Smad2 and Smad4, though additional experiments are needed to more fully reveal the mechanism details.…”

Section: Resultssupporting

confidence: 54%

Nephronectin Expression Is Up-Regulated by BMP-2

Kurosawa

Yamada

Suzuki

et al. 2016

Biological & Pharmaceutical Bulletin

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Nephronectin (Npnt), known to be a ligand of integrin α8β1, plays important roles in the development and function of various tissues, including those of the kidneys, liver, bones, and muscles. In previous studies, we showed that the expression of Npnt mRNA was regulated by various cytokines, including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), and oncostatin M (OSM), and that over-expression of Npnt enhanced osteoblast differentiation. In this study, we found that bone morphogenic protein-2 (BMP-2), known as an osteogenesis inducing cytokine, strongly up-regulated the expression of Npnt mRNA in a murine skeletal muscle cell line (C2C12) via the BMP-SMAD signaling pathway.

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Section: Resultssupporting

confidence: 54%

Nephronectin Expression Is Up-Regulated by BMP-2

Kurosawa

Yamada

Suzuki

et al. 2016

Biological & Pharmaceutical Bulletin

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“…Interestingly, these cells showed an increased basal Met phosphorylation when compared with the parental H69 along with upregulation of mesenchymal markers in vitro and in vivo and increased angiogenesis. The role of HGF as an inducer of EMT (10,25,26) and angiogenesis (27,28) has been reported previously.…”

Section: Discussionmentioning

confidence: 66%

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Cañadas

Rojo

Taus

et al. 2014

Clinical Cancer Research

116

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Purpose: Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/ Met-mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models.Experimental Design: SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N ¼ 87) and relapse (N ¼ 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome.Results: We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease.Conclusion: These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease. Clin Cancer Res; 20(4); 938-50. Ó2013 AACR.

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“…In contrast to Smad4À/À SCCs, Smad2À/À SCCs did not have increased expression of either TGFb or VEGF [91]. This suggests that tumors with reduced Smad2 expression may be susceptible to HGF-targeted treatment, a hypothesis supported by our study showing that short term treatment of Smad2À/À skin with a c-Met (HGF receptor) inhibitor reduces Smad2 loss-associated angiogenesis [91].…”

Section: Smad2 Loss and Cancermentioning

confidence: 56%

Two sides of the story? Smad4 loss in pancreatic cancer versus head‐and‐neck cancer

Malkoski

Wang

2012

FEBS Letters

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TGFβ signaling Smads (Smad2, 3, and 4) were suspected tumor suppressors soon after their discovery. Nearly two decades of research confirmed this role and revealed other divergent and cancer-specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context-specific as exemplified by pancreatic cancer and head-and-neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head-and-neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. The differing consequences of impaired Smad signaling in human cancers and the molecular mechanisms that underpin these differences will have important implications for the design and application of novel targeted therapies.

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

Cited by 15 publications

References 0 publications

Nephronectin Expression Is Up-Regulated by BMP-2

Nephronectin Expression Is Up-Regulated by BMP-2

Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

Two sides of the story? Smad4 loss in pancreatic cancer versus head‐and‐neck cancer

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