title: Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting β-catenin for degradation in pancreatic cancer.
abstract: Pancreatic cancer is one of the deadliest solid malignancies associated with aberrant Wnt signaling activation. Fbxw7 mutations have been implicated in the development of pancreatic cancer, whereas the exact mechanism of this ubiquitin ligase as a tumor suppressor remains unclear in pancreatic carcinogenesis. Here, we describe that Fbxw7 is downregulated upon pancreatic cancer development. Depletion of Fbxw7 results in tumor suppression in pancreatic cancer cells, while Fbxw7 overexpression inhibits pancreatic cancer cell proliferation and invasion. Considering the negative correlation between Fbxw7 and β-catenin, we find that Fbxw7 antagonizes Wnt signaling through targeting β-catenin for its degradation. Moreover, the inhibitory effect of Fbxw7 on pancreatic cancer cell proliferation is mainly executed by the destruction of the Wnt/β-catenin signaling pathway. We also reveal that c-myc, a widely accepted target of Fbxw7, is also transcriptionally regulated by the Fbxw7/β-catenin axis in pancreatic cancer cells. Collectively, our results demonstrate that Fbxw7 is a novel regulator of Wnt/β-catenin signaling-dependent regulation of pancreatic cancer cell growth and invasion, and inactivation of Fbxw7 in pancreatic cancer tissues might be the reason for the aberrant activation of Wnt signaling.
authors.affiliation: Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical College, Guiyang, 550001, China.
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Jiang
authors.affiliation: Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical College, Guiyang, 550001, China. chengyisun2014@163.com.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Sun
authors.affiliation: Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical College, Guiyang, 550001, China.
authors.forename: She
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical College, Guiyang, 550001, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical College, Guiyang, 550001, China.
authors.forename: Mei-Yuan
authors.initials: MY
authors.lastname: Chen
authors.affiliation: Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical College, Guiyang, 550001, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D012333:RNA, Messenger; D025801:Ubiquitin; D051153:Wnt Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases
keywords: Degradation; Fbxw7; Interaction; Pancreatic cancer; Wnt/β-catenin