Skip Navigation



Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm281
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrowOA All Versions of this Article:
29/3/480    most recent
bgm281v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Yoo, Y. A
Right arrow Articles by Cheul Oh, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yoo, Y. A
Right arrow Articles by Cheul Oh, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

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

Young A Yoo1, Myoung Hee Kang2, Jun Suk Kim3 and Sang Cheul Oh3

1 Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 136-705, Korea
2 Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Korea
3 Division of Oncology/Hematology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Korea

Corresponding author: Sang Cheul Oh, M.D., PhD, Assistant Professor of Internal Medicine, Address: Division of Oncology/Hematology, Korea University Guro Hospital, 97 Gurodong-gil, Guro-ku, Seoul, Korea, 152-703, Email: sachoh{at}korea.ac.kr, Phone: 2-2626-3060, Fax: 2-862-4453

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 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 cacer cells was reduced by treatment with anti-TGF-β blocking antibody or TGF-β1 siRNA in presence of N-Shh when compared to control groups. Furthermore, TGF-β1 secretion, TGF-β-mediated transcriptional response, expression of ALK5 (activin receptor-like kinase 5) protein, and phosphorylation of Smad 3 was 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 MMPs, 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 nonspecific 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.

Received July 24, 2007; revised November 25, 2007; accepted December 1, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
J. M. Bailey, B. J. Swanson, T. Hamada, J. P. Eggers, P. K. Singh, T. Caffery, M. M. Ouellette, and M. A. Hollingsworth
Sonic Hedgehog Promotes Desmoplasia in Pancreatic Cancer
Clin. Cancer Res., October 1, 2008; 14(19): 5995 - 6004.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.