Hedgehog signaling regulates hypoxia induced epithelial to mesenchymal transition and invasion in pancreatic cancer cells via a ligand-independent manner

Molecular Cancer

Research

Qing Sun¹  Jun Xu¹  Wanxing Duan¹  Jianjun Lei¹  Zheng Wu¹  Qingyong Ma¹  Qinhong Xu¹  Xuqi Li¹  Han Liu¹  Jiguang Ma²  Erxi Wu³ 

[1] Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, 277 West Yanta Road, 710061, Xi’an, Shaanxi Province, China;Department of Oncology, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, 277 West Yanta Road, 710061, Xi’an, Shaanxi Province, China;Department of Pharmaceutical Sciences, North Dakota State University, Sudro Hall 203, 58105, Fargo, ND, USA;

关键词: Hedgehog signaling;    Epithelial to mesenchymal transition;    Hypoxia;    Invasion;    Pancreatic cancer;   

DOI  :  10.1186/1476-4598-12-66

 received in 2013-03-28, accepted in 2013-06-18,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundHypoxia 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.MethodsPancreatic 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.ResultsHere, 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Lei et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.