title: E3 ubiquitin ligase FBW7α inhibits cholangiocarcinoma cell proliferation by downregulating c-Myc and cyclin E.
abstract: FBW7 (F-box and WD repeat domain-containing 7), also known as CDC4, AGO and SEL10, is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type E3 ubiquitin ligase. It is a recognized tumor suppressor because it targets multiple oncoproteins for ubiquitination-mediated destruction and its mutations are frequently identified in a variety of human malignancies. However, the function of FBW7 in proliferation of cholangiocarcinoma (CCA) remains unknown. We found that overexpression of FBW7α induced CCA cell arrest in G1 phase of cell cycle and inhibited cell proliferation in vitro and CCA xenograft tumor growth, suggesting that FBW7α is a tumor suppressor in CCA progression. Overxpression of FBW7α resulted in the protein degradation of its substrates such as c-Myc and cyclin E which promote CCA cell proliferation. Restoration of the expression of c-Myc, but not cyclin E, rescued the proliferation of FBW7α-overexpression CCA cells. These results suggest that FBW7α plays an essential inhibitory role in CCA progression, indicating that targeting FBW7α substrate c-Myc may be a potential strategy for CCA treatment.
authors.affiliation: Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Xiamen City Key Laboratory of Biliary Tract Diseases, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ouyang
authors.affiliation: Department of General Surgery, The First Hospital of Fuzhou, Fuzhou, Fujian, P.R. China.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xiang
authors.affiliation: Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Ti
authors.affiliation: Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Leihua
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Dan
authors.affiliation: Xiamen City Key Laboratory of Biliary Tract Diseases, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Chundong
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Pancreas and Vessel Surgery, Chenggong Hospital of Xiamen University, Xiamen, Fujian, P.R. China.
authors.forename: Wengang
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C489427:MYC protein, human; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases