Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway.

Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Research Abstract Details 

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Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Abstract Text:

Young A Yoo,Myoung Hee Kang,Jun Suk Kim,Sang Cheul Oh,

It is known that the activation of hedgehog (Hh) signaling is involved in the progression and invasion of various tumors, including gastric carcinoma. In this study, we investigated the impact of transforming growth factor (TGF)-beta signaling on the sonic hedgehog (Shh)-mediated invasion of gastric cancer cells. We found that higher concentrations of N-Shh enhanced cell motility and invasiveness in gastric cancer cells, whereas no increase was observed in cells that were treated with KAAD-cyclopamine (a Shh signaling inhibitor) or anti-Shh blocking antibodies. In addition, the N-Shh-induced migration and invasiveness of gastric cancer cells were reduced by treatment with anti-TGF-beta blocking antibody or TGF-beta1 small interfering RNA (siRNA) in presence of N-Shh when compared with control groups. Furthermore, TGF-beta1 secretion, TGF-beta-mediated transcriptional response, expression of activin receptor-like kinase (ALK) 5 protein and phosphorylation of Smad 3 were also enhanced by treatment with N-Shh, but not KAAD-cyclopamine, anti-Shh or TGF-beta1 blocking antibodies. Blockade of the ALK5 kinase in the presence of N-Shh significantly inhibited phosphorylation of Smad 3, activity of matrix metalloproteinases and Shh-induced cell motility/invasiveness. Importantly, transient expression of ALK5 siRNA or Smad 3 siRNA reduced the ability of N-Shh to stimulate migration and invasion of those cells compared with the cells treated with non-specific control siRNA. In summary, these results indicate that Shh promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Additionally, our findings are the first to suggest a role and mechanism for Shh signaling as it relates to the metastatic potential of gastric cancer, thereby indicating potential therapeutic molecular targets to decrease metastasis.

Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Publishing Authors By Initials

YA Yoo,MH Kang,JS Kim,SC Oh,

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Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Carcinogenesis

VOLUME: 29

Page Numbers: 480-90

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ISSN: 1460-2180

DAY: 3

MONTH: 01

YEAR: 2008

Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Information

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LANGUAGE: eng

NlmUniqueID: 8008055

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Grant and Affiliation Information for Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway.

AFFILIATION: Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 136-705, Korea.

Country: England

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MEDLINETA: Carcinogenesis

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