Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(3):480-490; doi:10.1093/carcin/bgm281
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Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-β-mediated activation of the ALK5–Smad 3 pathway
Brain Korea 21 Program for Biomedical Science
1 Graduate School of Medicine
2 Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Korea
* To whom correspondence should be addressed. Division of Oncology/Hematology, Korea University Guro Hospital, 97 Gurodong-gil, Guro-ku, Seoul 152-703, Korea; Tel: +82 2 2626 3060; Fax: +82 2 862 4453; Email: sachoh{at}korea.ac.kr
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)-β 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-β blocking antibody or TGF-β1 small interfering RNA (siRNA) in presence of N-Shh when compared with control groups. Furthermore, TGF-β1 secretion, TGF-β-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-β1 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-β-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.
Abbreviations: ALK, activin receptor-like kinase; Hh, hedgehog; MMP, matrix metalloproteinase; PBS, phosphate-buffered saline; siRNA, small interfering RNA; smo, smoothened; Shh, sonic hedgehog; TGF, transforming growth factor; TβRII, TGF-β type II receptor
Received July 24, 2007; revised November 25, 2007; accepted December 1, 2007.
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