Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis
Authors
Morton, Jennifer P.Mongeau, Michelle E.
Klimstra, David S.
Morris, John P.
Lee, Yie Chia
Kawaguchi, Yoshiya
Wright, Christopher V. E.
Hebrok, Matthias
Lewis, Brian C.
Document Type
Journal ArticlePublication Date
2007-03-21Keywords
AnimalsCell Cycle Proteins
Cell Proliferation
Cell Survival
Cell Transformation, Neoplastic
Cell Transplantation
Epithelial Cells
Epithelium
Gene Expression Regulation
Genes, ras
Hedgehog Proteins
Mice
Pancreatic Ducts
Pancreatic Neoplasms
RNA, Messenger
Signal Transduction
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Activation of sonic hedgehog (Shh) signaling occurs in the majority of pancreatic ductal adenocarcinomas. Here we investigate the mechanisms by which Shh contributes to pancreatic tumorigenesis. We find that Shh expression enhances proliferation of pancreatic duct epithelial cells, potentially through the transcriptional regulation of the cell cycle regulators cyclin D1 and p21. We further show that Shh protects pancreatic duct epithelial cells from apoptosis through the activation of phosphatidylinositol 3-kinase signaling and the stabilization of Bcl-2 and Bcl-X(L). Significantly, Shh also cooperates with activated K-Ras to promote pancreatic tumor development. Finally, Shh signaling enhances K-Ras-induced pancreatic tumorigenesis by reducing the dependence of tumor cells on the sustained activation of the MAPK and phosphatidylinositol 3-kinase/Akt/mTOR signaling pathways. Thus, our data suggest that Shh signaling contributes to tumor initiation in the pancreas through at least two mechanisms and additionally enhances tumor cell resistance to therapeutic intervention. Collectively, our findings demonstrate crucial roles for Shh signaling in multiple stages of pancreatic carcinogenesis.Source
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5103-8. Epub 2007 Mar 19. Link to article on publisher's site
DOI
10.1073/pnas.0701158104Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38485PubMed ID
17372229Related Resources
ae974a485f413a2113503eed53cd6c53
10.1073/pnas.0701158104