ACTIVATION OF THE HEDGEHOG-PATCHED-SIGNALING PATHWAY IN PANCREATIC ADENOCARCINOMAS

Abstract

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). In cell lines derived from pancreatic adenocarcinomas this pathway activity can be reverted by cyclopamine, a specific antagonist of the pathway resulting in apoptosis and reduction of cell proliferation. To investigate if alterations of PTCH may also be involved in the pathogenesis of pancreatic adenocarcinomas we screened 26 tumors for mutations using single-strand conformation polymorphism analysis (SSCP) of all coding exons and direct sequencing. We uncovered single nucleotide polymorphisms (SNPs) in exon 2, 11, 12 and 22 of the PTCH gene but no somatic mutations. Furthermore, the expression levels of known hedgehog target genes were determined using the competitive RT-PCR method. A total of 21 pancreatic adenocarcinoma biopsies and 3 pancreatic cancer cell lines were analyzed. In the majority of pancreatic cancer we found significant overexpression of the target genes GLI-1 and PTCH compared to the corresponding normal pancreatic tissue. The findings indicate that the hedgehog signaling pathway is frequently activated in pancreatic adenocarcinomas.