Hedgehog signaling is activated in subsets of esophageal cancers

Abstract

The hedgehog pathway plays a critical role in the development of the foregut. However, the role of the hedgehog pathway in primary esophageal cancers is not well studied. Here, we report that elevated expression of hedgehog target genes occurs in 14 of 22 primary esophageal cancers. The hedgehog signaling activation is not associated with tumor subtypes, stages, or differentiation. While the sonic hedgehog (Shh) transcript is localized to the tumor tissue, expression of Gli1 and PTCH1 is observed both in the tumor and in the stroma. We discovered that 4 esophageal squamous cell carcinomas, which overexpress Shh, have genomic amplification of the Shh gene. Treatment of esophageal cancer cells with smoothened antagonist, KAAD‐cyclopamine, or the neutralizing antibodies of Shh reduces cell growth and induces apoptosis. Overexpression of Gli1 under the CMV promoter renders these cells resistant to the treatments. Thus, our results indicate that elevated expression of Shh and its target genes is quite common in esophageal cancers. Our data also indicate that downregulation of Gli1 expression may be an important mechanism by which KAAD‐cyclopamine inhibits growth and induces apoptosis in esophageal cancer cells (supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020‐7136/suppmat/index.html). © 2005 Wiley‐Liss, Inc.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Studies also indicate that Hh signaling may be involved in different stages of carcinogenesis in different tumors. In pancreatic and esophageal cancers for example, activation of this pathway is found in both early tumors and metastatic cancer (Bailey et al, 2009;Feldmann et al, 2008;Ma et al, 2006;Pasca di Magliano and Hebrok, 2003), suggesting that Hh signaling has a significant role in carcinogenesis of these tumors. In support of these findings, transgenic mice with pancreatic-specific expression of SHH or (Sheng et al, 2004).…”

Hedgehog signaling pathway and gastrointestinal stem cell signaling network (Review)

“…SHH was expressed in primary esophageal cancer, and SHH gene was amplified in some of the cases. Elevated expression of Hedgehog target genes occured in 14 out of 22 primary esophageal cancer (54).…”

Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas

“…Immunohistochemistry was performed according to the protocol described by Ma et al [16,17] . Antigen unmasking was achieved by boiling sections in 0.01 mol/L sodium citrate; pH 6.0, for 10 min.…”

“…More recently, small-cell lung cancer (SCLC), prostate cancer and pancreatic adenocarcinoma have been linked to Hh signaling pathway, providing a molecular mechanism for these aggressive diseases [13][14][15] . Dysregulation of Hh signaling pathway may also play a role in gastrointestinal (GI) tumors [16,17] . To better understand the mechanism of colorectal adenocarcinoma, a common cancer worldwide, we examined here the expression of several key molecules functioned in the Hh signaling pathway at protein and mRNA levels.…”