Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner
Open Access
- 20 June 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Cancer
- Vol. 12 (1), 66-11
- https://doi.org/10.1186/1476-4598-12-66
Abstract
Background Hypoxia plays a vital role in cancer epithelial to mesenchymal transition (EMT) and invasion. However, it is not quite clear how hypoxia may contribute to these events. Here we investigate the role of Hedgehog (Hh) signaling in hypoxia induced pancreatic cancer EMT and invasion. Methods Pancreatic cancer cells were cultured under controlled hypoxia conditions (3% O2) or normoxic conditions. HIF-1α siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1α transcription or Hh signaling activation. The effect of hypoxia and Hh signaling on cancer cell EMT and invasion were evaluated by Quantitative real-time PCR analysis, Western blot analysis and invasion assay. Results Here, we show that non-canonical Hh signaling is required as an important role to switch on hypoxia-induced EMT and invasion in pancreatic cancer cells. Moreover, our data demonstrate hypoxia induces EMT process as well as invasion, and activates the non-canonical Hh pathway without affecting sonic hedgehog homolog (SHH) expression. Moreover, these effects are reversible upon HIF-1α siRNA interference with unchanged SHH and patched1 (PTCH1) level. Furthermore, our data demonstrate that hypoxia induced invasion and EMT process are effectively inhibited by Smoothened (SMO) antagonist cyclopamine and GLI1 siRNA. In addition, GLI1 interference inhibited EMT progress with significantly suppressed vimentin expression, whereas inhibition of SMO through cyclopamine could not reduce vimentin level. This data indicate that hypoxia could trigger other factors (such as TGF-β, KRAS or RTK) bypassing SMO to activate GLI1 directly. Conclusions Our findings suggest that Hh signaling modulates hypoxia induced pancreatic cancer EMT and invasion in a ligand-independent manner. Thus, Hh signaling may represent a promising therapeutic target for preventing pancreatic cancer progression.Keywords
This publication has 45 references indexed in Scilit:
- Genetics and biology of pancreatic ductal adenocarcinomaGenes & Development, 2006
- Regulation of E-cadherin Expression by VHL and Hypoxia-Inducible FactorCancer Research, 2006
- Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cellsHepatology, 2005
- Molecular requirements for epithelial–mesenchymal transition during tumor progressionCurrent Opinion in Cell Biology, 2005
- The Snail genes as inducers of cell movement and survival: implications in development and cancerDevelopment, 2005
- HIF1 and oxygen sensing in the brainNature Reviews Neuroscience, 2004
- Hypoxia Attenuates the Expression of E-Cadherin via Up-Regulation of SNAIL in Ovarian Carcinoma CellsThe American Journal of Pathology, 2003
- Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding proteinNature, 1999
- Dual Roles for Patched in Sequestering and Transducing HedgehogCell, 1996
- The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehogNature, 1996