Journal
CANCER RESEARCH
Volume 72, Issue 1, Pages 88-99Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-4621
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Funding
- LOEWE
- Mayo Clinic Cancer Center [NCI CA136526]
- Mayo Clinic Pancreatic SPORE [P50 CA102701]
- Mayo Clinic Center for Cell Signaling in Gastroenterology [P30 DK084567]
- NIH [CA136526, CA102701, DK084567, K07 116303]
- RRW [K07 116303]
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The Hedgehog (HH) pathway has been identified as an important deregulated signal transduction pathway in pancreatic ductal adenocarcinoma (PDAC), a cancer type characterized by a highly metastatic phenotype. In PDAC, the canonical HH pathway activity is restricted to the stromal compartment while HH signaling in the tumor cells is reduced as a consequence of constitutive KRAS activation. Here, we report that in the tumor compartment of PDAC the HH pathway effector transcription factor GLI1 regulates epithelial differentiation. RNAi-mediated knockdown of GLI1 abolished characteristics of epithelial differentiation, increased cell motility, and synergized with TGF beta to induce an epithelial-to-mesenchymal transition (EMT). Notably, EMT conversion in PDAC cells occurred in the absence of induction of SNAIL or SLUG, two canonical inducers of EMT in many other settings. Further mechanistic analysis revealed that GLI1 directly regulated the transcription of E-cadherin, a key determinant of epithelial tissue organization. Collectively, our findings identify GLI1 as an important positive regulator of epithelial differentiation, and they offer an explanation for how decreased levels of GLI1 are likely to contribute to the highly metastatic phenotype of PDAC. Cancer Res; 72(1); 88-99. (C) 2011 AACR.
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