FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells.
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.
Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, China.
Hui
H
Yang
Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, China.|Department of General Surgery, Jinan Central Hospital of Shandong University, Jinan, China.
Xiaofei
X
Lu
Department of Emergency Medicine, Jinan Fifth People's Hospital, Jinan, China.
Ziming
Z
Liu
Department of Pathology, Jinan Fourth People's Hospital, Jinan, China.
Lili
L
Chen
Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, China.
Yunfei
Y
Xu
Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Jinan, China.
Yuli
Y
Wang
Department of Anatomy and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Jinan, China.
Guangwei
G
Wei
Department of Hepatobiliary Surgery, Qilu Hospital of Shandong University, Jinan, China.
Yuxin
Y
Chen
D000818:Animals; D001650:Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology*; D015398:Signal Transduction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D044767:Ubiquitin-Protein Ligases
ZEB1; mTOR; metastasis; tumor suppressor; ubiquitin ligase