Sonic Hedgehog-Gli1 Signaling Pathway Regulates the Epithelial Mesenchymal Transition (EMT) by Mediating a New Target Gene, S100A4, in Pancreatic Cancer Cells

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.

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

“…Numerous lines of evidence have shown aberrant activation of the Shh signaling pathway in cancer patients and drug intervention to block the transduction has resulted in tumor shrinking and cancer cell apoptosis in numerous types of solid tumor (12)(13)(14). In vivo and in vitro, pancreatic cancer cells have a lower proliferative and a higher apoptotic rate after intervention with an Shh antagonist (15,16). Following suppression by a specific inhibitor, malignant hepatic neoplasms also display a reduction in the degree of malignancy, such as slower proliferation and higher vulnerability to chemotherapy (17,18).…”

Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor–stromal cross-talk

“…In addition, pancreatic tumors from HNKtreated group exhibited decreased desmoplasia as confirmed by immunostaining of extracellular matrix and myofibroblast marker proteins. Expression of CXCR4 and sonic hedgehog (SHH), two known promoters of tumor growth, metastasis and desmoplasia (13)(14)(15)(16)(17), was reduced in HNK-treated pancreatic tumor xenografts and in cancer cell lines in vitro. Further biochemical studies suggested the role of nuclear factor-kappaB (NF-κB) in suppression of CXCR4 and SHH expression.…”

Curcumin increases efficiency of γ-irradiation in gliomas by inhibiting Hedgehog signaling pathway

“…39 There are also numbers of research revealed that Curcumin has specific regulation to Hedgehog signaling pathway and EMT process 7,40,41 in several cancer cells including pancreas, colon, leukemia, prostate carcinoma and glioblastomas. 8,[42][43][44] Islam SS et al and Xu X et al 9,10 point out that the Hedgehog signaling pathway activates EMT process to promote tumorigenicity and stemness. It is potent that Tsai, C. L.…”

“…7,8 And Curcumin could also prevent the EMT in different tumor cells. 9,10 With the interruption of EMT, Curcumin might cover the shortage of g-irradiation (induction of EMT). In this research, we had experiments on LN229 and U251 cells, which represented to be sensitive and insensitive to cytotoxic effect of g-irradiation, respectively.…”