Article
Sonic Hedgehog(SHH) in pancreatic cancer: Effect of the small molecule inhibitor Hh-Antag
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Published: | March 20, 2006 |
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Activation of the hedgehog signal transduction pathway, triggered by hedgehog binding to the transmembrane receptor PTCH or by mutations in the PTCH gene, plays an important role in the development of various tumors including cutaneous basal cell carcinomas and cerebellar medulloblastomas. Recent findings indicate that digestive tract tumors including pancreatic adenocarcinomas also display increased hedgehog signaling activity due to an abnormal expression of the secreted hedgehog ligand sonic hedgehog (Shh). To investigate if alterations of PTCH may also be involved in the pathogenesis of pancreatic adenocarcinomas we screened 38 tumors and 3 cell lines for mutations using single-strand conformation polymorphism analysis (SSCP) of all coding exons and direct sequencing. Furthermore, the expression levels of known hedgehog target genes were determined using the competitive RT-PCR method. A total of 26 pancreatic adenocarcinoma biopsies and 3 pancreatic cancer cell lines as well as constitutional normal pancreatic tissue were analyzed. In the majority of pancreatic cancers we found significant overexpression of the target genes GLI-1 and PTCH compared to the corresponding normal pancreatic tissue. Additionally the effects of the small molecule inhibitor of the Hedgehog-Patched pathway Hh-Antag (G-024856; CUR) were investigated. Hh-Antag inhibits the function of Smoothened in pancreatic cancer cells; this results in inhibition of cell proliferation.