Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis Journal Article
| Authors: | Morton, J. P.; Mongeau, M. E.; Klimstra, D. S.; Morris, J. P.; Yie, C. L.; Kawaguchi, Y.; Wright, C. V. E.; Hebrok, M.; Lewis, B. C. |
| Article Title: | Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis |
| Abstract: | 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-XL. 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. © 2007 by The National Academy of Sciences of the USA. |
| Keywords: | signal transduction; mitogen activated protein kinase; protein expression; unclassified drug; genetics; nonhuman; pancreatic neoplasms; protein function; cell proliferation; cell cycle protein; animal cell; mouse; animal; cytology; metabolism; animals; cell cycle proteins; mice; cell survival; protein bcl 2; apoptosis; sonic hedgehog protein; animal experiment; animal model; hedgehog proteins; protein stability; enzyme activation; pathology; protein bcl xl; transplantation; phosphatidylinositol 3 kinase; carcinogenesis; cancer resistance; cell transformation, neoplastic; gene expression regulation; transcription regulation; messenger rna; rna, messenger; cell transformation; pancreas duct; pancreas tumor; pancreatic ducts; epithelium cell; epithelial cells; pancreas adenocarcinoma; pancreatic cancer; epithelium; genes, ras; cyclin d1; k ras protein; protein p21; erinaceidae; oncogene ras; shh protein, mouse; cell transplantation; mouse model; k-ras; shh |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 104 |
| Issue: | 12 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2007-03-20 |
| Start Page: | 5103 |
| End Page: | 5108 |
| Language: | English |
| DOI: | 10.1073/pnas.0701158104 |
| PUBMED: | 17372229 |
| PROVIDER: | scopus |
| PMCID: | PMC1828712 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 86" - "Export Date: 17 November 2011" - "CODEN: PNASA" - "Source: Scopus" |
