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Carcinogenesis Advance Access published online on May 19, 2005
Carcinogenesis, doi:10.1093/carcin/bgi130
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Published by Oxford University Press 2005
Received January 28, 2005
Revised May 4, 2005
Accepted May 13, 2005

CANCER BIOLOGY

Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas

Xiaoli Ma 1, Kai Chen 2, Shuhong Huang 1, Xiaoli Zhang 2, Patrick A. Adegboyega 3, B. Mark Evers 4, Hongwei Zhang 1, and Jingwu Xie 2*

1 Institute of Developmental Biology, School of Life Sciences, Shandong University, Jinan, P.R. China
2 Sealy Center for Cancer Cell Biology, Department of Pharmacology, University of Texas Medical Branch, Galveston, Texas 77555-1048
3 Sealy Center for Cancer Cell Biology, Department of Pathology, University of Texas Medical Branch, Galveston, Texas 77555-1048
4 Sealy Center for Cancer Cell Biology, Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555-1048

* To whom correspondence should be addressed.
Jingwu Xie, E-mail: jinxie{at}utmb.edu


  Abstract

The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that hedgehog pathway activation occurs in the stomach and other gastrointestinal cancers. However, the association of hedgehog pathway activation with tumor stage, differentiation and tumor subtype is not well documented. Here, we report our findings that elevated expression of hedgehog target genes PTCH1 or Gli1 occurs in 63 of 99 primary gastric cancers. Activation of the hedgehog pathway is associated with poorly differentiated and more aggressive tumors. The sonic hedgehog (Shh) transcript is localized to the cancer tissue, whereas expression of Gli1 and PTCH1 is observed both in the cancer and in the surrounding stroma. Treatment of gastric cancer cells with KAAD-cyclopamine, a hedgehog signaling inhibitor, decreases expression of Gli1 and PTCH1, resulting in cell growth inhibition and apoptosis. Over-expression of Gli1 under the control of the CMV promoter renders these cells resistant to cyclopamine-induced apoptosis. Thus, our analysis of in vivo tissues indicates that the hedgehog pathway is frequently activated in advanced gastric adenocarcinomas; our in vitro studies suggest that hedgehog signaling contributes to gastric cancer cell growth. These data predict that targeted inhibition of the hedgehog pathway may be effective in the prevention and treatment of advanced gastric adenocarcinomas.


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