期刊
GENES & DEVELOPMENT
卷 23, 期 1, 页码 24-36出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1753809
关键词
Pancreatic ductal adenocarcinoma; PDAC; hedgehog; Gli; Smoothened; pancreatic cancer
资金
- NIH [DK6053301A1, CA112537-01]
- PANCAN Career Development Award for Pancreatic Cancer Research [CA125127]
- Mayo Clinic Pancreatic SPORE [P50 CA102701]
- University of Iowa/Mayo Clinic Lymphoma SPORE [P50 CA097274]
- Damon Runyon Cancer Research Foundation [DRG-1831-04]
- NATIONAL CANCER INSTITUTE [R01CA136526, P50CA097274, R01CA112537, R03CA125127, P50CA102701] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK060533] Funding Source: NIH RePORTER
Pancreatic ductal adenocarcinoma (PDAC) is characterized by the deregulation of the hedgehog signaling pathway. The Sonic Hedgehog ligand (Shh), absent in the normal pancreas, is highly expressed in pancreatic tumors and is sufficient to induce neoplastic precursor lesions in mouse models. We investigated the mechanism of Shh signaling in PDAC carcinogenesis by genetically ablating the canonical bottleneck of hedgehog signaling, the transmembrane protein Smoothened (Smo), in the pancreatic epithelium of PDAC-susceptible mice. We report that multistage development of PDAC tumors is not affected by the deletion of Smo in the pancreas, demonstrating that autocrine Shh-Ptch-Smo signaling is not required in pancreatic ductal cells for PDAC progression. However, the expression of Gli target genes is maintained in Smo-negative ducts, implicating alternative means of regulating Gli transcription in the neoplastic ductal epithelium. In PDAC tumor cells, we find that Gli transcription is decoupled from upstream Shh-Ptch-Smo signaling and is regulated by TGF-beta and KRAS, and we show that Gli1 is required both for survival and for the KRAS-mediated transformed phenotype of cultured PDAC cancer cells.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据