Sonic Hedgehog Signaling Pathway in Pancreatic Cystic Neoplasms and Ductal Adenocarcinoma

Abstract

Hedgehog (Hh) signaling is an important mediator of tumorigenesis of pancreatic ductal adenocarcinoma (PA). It is intriguing to explore whether Hh signaling is also involved in pancreatic cystic neoplasms, which are phenotypically different from PA. Patients with solid and pseudopapillary tumor (SPT; n = 12), mucinous cystic neoplasm (MCN; n = 18), intraductal papillary mucinous neoplasm (IPMN; n = 18), and PA (n = 20) were studied. Expression of Hh signaling molecules including sonic Hh (sHh), smoothened (Smo), patched 1 (Ptc1), and Gli were determined using immunohistochemistry and/or Western blotting. Cell cycle-regulator genes, including cyclin A, B, C, and D1 messenger RNA, were determined using ribonuclease protection assay. Six of 12 SPT, 8 of 18 MCN, 17 of 18 IPMN, and 20 of 20 PA displayed Hh signaling using immunohistochemistry. Sonic Hh was predominantly expressed in stromal cells neighboring to the neoplastic cells of SPT and IPMN; in contrast, sHh was expressed in both stromal cells and neoplastic epithelial cells of MCN and PA. The quantitative expression of sHh signaling detected by Western blotting showed that expression of Ptc1 and Gli, but not Smo, corresponded to the magnitude of sonic hedgehog ligand. The expression of cyclin D1 messenger RNA was highest in PA, followed by MCN, IPMN, and SPT, which matches with Ptc1 and Gli. Hedgehog signaling pathway might play a role during tumorigenesis of SPT, MCN, IPMN, and PA. Mucinous cystic neoplasm and PA exhibit an autocrine regulation of sHh, whereas SPT and IPMN do not. Overexpression of Ptc1 and Gli, reflected by cyclin D1, might represent proliferative potential of various pancreatic neoplasms.