Journal Article

Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas

Xiaoli Ma, Kai Chen, Shuhong Huang, Xiaoli Zhang, Patrick A. Adegboyega, B.Mark Evers, Hongwei Zhang and Jingwu Xie

in Carcinogenesis

Volume 26, issue 10, pages 1698-1705
Published in print October 2005 | ISSN: 0143-3334
Published online May 2005 | e-ISSN: 1460-2180 | DOI:
Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas

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The hedgehog pathway plays a critical role in the development of the foregut. Recent studies indicate that the 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 the elevated expression of hedgehog target genes human patched gene 1 (PTCH1) or Gli1 occurs in 63 of the 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. Overexpression of Gli1 under the control of the cytomegalovirus (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.

Keywords: BCC, basal cell carcinoma; CMV, cytomegalovirus; PTC, patched; PTCH1, human patched gene 1; Shh, sonic hedgehog; SMO, smoothened; Su(Fu), suppressor of fused

Journal Article.  4496 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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