RRC ID 67487
Author Yang H, Lu X, Liu Z, Chen L, Xu Y, Wang Y, Wei G, Chen Y.
Title FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells.
Journal Oncotarget
Abstract Epithelial-mesenchymal transition (EMT) plays a fundamental role in cancer metastasis. The ubiquitin ligase FBXW7, a general tumor suppressor in human cancer, has been implicated in diverse cellular processes, however, its role in cholangiocarcinoma (CCA) metastasis has not been identified. Here, we report a crucial role of FBXW7 in CCA metastasis by regulating EMT. Loss of FBXW7 expression was detected in CCA cells and clinical specimens. Clinicopathological analysis revealed a close correlation between FBXW7 deficiency and metastasis, TNM stage and differentiation in intrahepatic CCA and perihilar CCA. Moreover, FBXW7 silencing in CCA cells dramatically promoted EMT, stem-like capacity and metastasis both in vitro and in vivo. Conversely, FBXW7 overexpression attenuated these processes. Mechanistically, treatment with rapamycin, a mTOR inhibitor, inhibited EMT, stem-like capacity and metastasis induced by FBXW7 silencing both in vitro and in vivo. Furthermore, the expression of EMT regulating transcription factors, snail, slug and ZEB1, were also decreased markedly with rapamycin treatment. In addition, silencing ZEB1 inhibited EMT and metastasis of both CCA cells and FBXW7 deficient CCA cells, which implicated the potential role of ZEB1 in FBXW7/mTOR signaling pathway related CCA metastasis. In conclusion, our findings defined a pivotal function of FBXW7 in CCA metastasis by regulating EMT.
Volume 6(8)
Pages 6310-25
Published 2015-3-20
DOI 10.18632/oncotarget.3355
PII 3355
PMID 25749036
PMC PMC4467439
MeSH Animals Bile Duct Neoplasms / enzymology Bile Duct Neoplasms / genetics Bile Duct Neoplasms / pathology* Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism Cell Cycle Proteins / physiology* Cell Line, Tumor Cholangiocarcinoma / enzymology Cholangiocarcinoma / genetics Cholangiocarcinoma / pathology* Epithelial-Mesenchymal Transition / physiology* F-Box Proteins / genetics F-Box Proteins / metabolism F-Box Proteins / physiology* F-Box-WD Repeat-Containing Protein 7 Heterografts Humans Male Mice Mice, Nude Neoplasm Metastasis Neoplastic Stem Cells / enzymology Neoplastic Stem Cells / pathology* Signal Transduction Transfection Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism Ubiquitin-Protein Ligases / physiology*
IF 5.168
Human and Animal Cells HuCCT1(RCB1960)