Abstract
AimsThe 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.MethodsOn 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.ResultsFive 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).ConclusionOur 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.
Highlights
Pancreatic cancer represents one of the leading causes of cancer-related mortality in industrialized countries [1]
To delineate the gene expression induced by sonic hedgehog (Shh)-Gli1 signals in pancreatic cancer cells, AsPC-1 cells were used to cDNA microarray assays comparing lentivirus-control vs lentivirus-Gli1i cells
When focusing on the epithelial mesenchymal transition (EMT)-related genes in cDNA data, we found the positive relationship between Shh signals and S100 genes family[21]
Summary
Pancreatic cancer represents one of the leading causes of cancer-related mortality in industrialized countries [1]. A large number of studies have shown that the epithelial mesenchymal transition (EMT) might be a key mechanism of pancreatic cancer cells detaching from the primary tumor site and spreading to distant organs. Hedgehog (Hh) signaling pathway has been demonstrated to be an important promoter of tumor growth in several gastrointestinal tract cancers [4,5]. A large number of studies have shown that the main mechanisms of Hh signaling pathway in cancer cells were to promote epithelial mesenchymal transition (EMT) process [9,10,11]. It has been demonstrated that blocking this pathway significantly inhibited metastasis of tumor cells in vivo and in xenograft models [12,13]
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