title: Sonic hedgehog-Gli1 signaling pathway regulates the epithelial mesenchymal transition (EMT) by mediating a new target gene, S100A4, in pancreatic cancer cells.
abstract: OBJECTIVE
  The hedgehog signaling pathway plays an important role in EMT of pancreatic cancer cells, but the precise mechanisms remain elusive. Because S100A4 as a key EMT moleculer marker was found to be upregulated upon Gli1 in pancreatic cancer cells, we focused on the relationship between Shh-Gli1 signals and S100 genes family.
  
  
  METHODS
  On the base of cDNA microarray data, we investigated regulating mechanism of Gli1 to some members of S100A genes family in pancreatic cancer cell lines firstly. Then, the regulation of Gli1 to S100A4 gene was studied by molecular biology assays and the pro-metastasis effection of Gli1-dependent S100A4 was investigated in vitro. Finally, the expressions of Shh, Gli1, S100A4 and E-cadherin in pancreatic cancer tissues were studied by using immunohistochemistry assays.
  
  
  RESULTS
  Five members of the S100 genes family, S100A2, S100A4, S100A6, S100A11, and S100A14 were found to be downregulated significantly upon Gli1 knockdown. Gli1 enhancer prediction combining with in vitro data demonstrated that Gli1 primarily regulates S100A family members via cis-acting elements. Indeed, the data indicate S100A4 and vimentin genes were upregulated significantly by Shh/Gli1-expression increasing and E-cadherin was significantly reduced at the same time. Migration of PC cells was increased significantly in a dose-dependent manner of Gli1 expression (P<0.05) and siS100A4 significantly reversed the response of PC cells induced by L-Shh transduction (P<0.01).
  
  
  CONCLUSIONS
  Our data establish a novel connection between Shh-Gli1 signaling and S100A4 regulation, which imply that S100A4 might be one of the key factors in EMT mediated by Shh-Gli1 signaling in pancreatic cancer.
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Xuanfu
authors: X
authors: Xu
authors: Department of Endocrinology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Bin
authors: B
authors: Su
authors: Department of Gastroenterology, the Second Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China.
authors: Chuangao
authors: C
authors: Xie
authors: Department of Gastroenterology, the Second Hospital of Zhejiang University, Hangzhou, Zhejiang Province, China.
authors: Shumei
authors: S
authors: Wei
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Yingqun
authors: Y
authors: Zhou
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Hua
authors: H
authors: Liu
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Weiqi
authors: W
authors: Dai
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Ping
authors: P
authors: Cheng
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Fan
authors: F
authors: Wang
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Xiaorong
authors: X
authors: Xu
authors: Department of Gastroenterology, the Tenth People's Hospital of Shanghai, Tongji University, Shanghai, China.
authors: Chuanyong
authors: C
authors: Guo
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D019073:HT29 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D015820:Cadherins; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D034741:RNA, Small Interfering; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D014157:Transcription Factors; D014746:Vimentin; D000071676:Zinc Finger Protein GLI1; C077591:S100A4 protein, human