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FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3?/?- catenin signaling cascade via FGFR4 activation.

ABSTRACT: Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E-cadherin in HCC tissues and cell lines. Ectopic FGF19 expression promotes EMT and invasion in epithelial-like HCC cells through repression of E-cadherin expression, whereas FGF19 knockdown enhances E-cadherin expression and hence diminishes EMT traits in mesenchymal-like HCC cells, suggesting FGF19 exerts its tumor progressing functions as an EMT inducer. Interestingly, depletion of FGF19 cannot abrogate EMT traits in the presence of GSK3? inhibitors. Furthermore, FGF19-induced EMT can be markedly attenuated when FGFR4 is knocked out. These observations clearly indicate that FGFR4/GSK3?/?-catenin axis may play a pivotal role in FGF19-induced EMT in HCC cells. As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC.

SUBMITTER: Zhao H

PROVIDER: S-EPMC4924662 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation.

Zhao Huakan H Lv Fenglin F Liang Guizhao G Huang Xiaobin X Wu Gang G Zhang Wenfa W Yu Le L Shi Lei L Teng Yong Y

Oncotarget 20160301 12

Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E-cadherin in HCC tissues and cell l ...[more]

PMID: 26498355

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Project description:BackgroundThe ubiquitin E3 ligase activity has been ascribed to MID1, the causative gene of X-linked OS, and its homologue, MID2. Both alpha4, the common MID protein partner, and PP2Ac in MID-alpha4-PP2Ac complexes can be ubiquitylated. Ubiquitylation of alpha4 converted its function toward PP2Ac from protective to destructive, while PP2A also affected MID protein phosphorylation and their subsequent trafficking on microtubules. It was believed that disruption of the function of MID1-alpha4-PP2A complex was vital to the pathogenesis of craniofacial malformation, the most prominent clinical manifestation of OS, although the detailed molecular mechanisms was not unravelled.MethodsThe cellular level of PP2A and phosphor-PP2A in cells overexpressing MID1/MID2 or in cells with siRNA mediated MID1/MID2 gene silencing was analyzed using Western blot. The Wnt signaling in these cells was further monitored using TCF/LEF luciferase reporter assay and the cellular level of β-catenin was also verified using western blot. Given the crosstalk of E-cadherin and Wnt via the common effector β-catenin, the potential influences of MID1/MID2 on the cell migration and epithelial-mesenchymal transition (EMT) were investigated using wound healing assay and immunofluorescence for E-cadherin and vimentin, respectively.ResultsHere, we presented the increased phosphorylation of PP2Ac in cells overexpressing MID1/MID2, and vice versa, in vitro, while the cellular level of total PP2Ac was unaffected. In addition, β-catenin, the effector of canonical Wnt signaling, was downregulated in cells overexpressing MID1/MID2 and upregulated in cells with siRNA mediated MID1/MID2 gene silencing. Down-regulated Wnt/β-catenin signaling by Okadaic acid, a specific inhibitor of PP2A, was partially rescued by siRNA mediated MID1/MID2 gene silencing. In consistent, an activated EMT and accelerated cell migration in cells with MID1/MID2 gene silencing were observed, and vice versa.ConclusionsThe results in this study indicated roles for MID1 and MID2 in regulating cell migration/EMT via modulating Wnt/β-catenin signaling, which might help to understand the molecular etiology of the facial abnormalities that are usually the consequences of defective neural crest cells migration and EMT at the early stage of craniofacial development.

Dataset Information

FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3?/?- catenin signaling cascade via FGFR4 activation.

Publications

FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation.

Similar Datasets

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