title: Significance of epithelial growth factor in the epithelial-mesenchymal transition of human gallbladder cancer cells.
abstract: Five gallbladder cancer (GBC) cell lines were examined for morphological changes in collagen gel culture. GBh3 and HUCCT-1 cells formed tubules in response to treatment with epithelial growth factor (EGF) and hepatocyte growth factor (HGF), and showed high levels of expression of E-cadherin (ECD), and low levels of SNAIL, vimentin, transforming growth factor (TGF)-β, and nucleostemin (NS). In contrast, the GBd15 and FU-GBC-1 cell lines treated with EGF and HGF showed a scattering phenotype, and expressed low levels of ECD and high levels of SNAIL, vimentin, TGF-β, and NS. All cell lines expressed the EGF receptor, c-Met, EGF, and TGF-α, but not HGF. Transforming growth factor-β was upregulated by EGF. Knockdown of the EGF receptor abrogated both tubule formation and scattering, whereas KD of TGF-β abrogated only scattering. Knockdown of EGF induced nuclear translocation of β-catenin and Wnt-related NS induction in the scattering cell lines, but not in the tubule-forming cell lines, whereas KD of glycogen synthase kinase-3β in the tubule-forming cell lines resulted in the nuclear translocation of β-catenin and Wnt-related NS induction in response to EGF treatment. These results suggest that EGF enhances epithelial-mesenchymal transformation and acquisition of stemness in GBC cells with a scattering phenotype through the activity of β-catenin. Repression of ECD in scattering GBC cells induced the release of β-catenin from the cell adhesion complexes along the plasma membrane and its translocation to the nucleus to activate Wnt signaling, which upregulated NS.
authors.affiliation: Department of Gastroenterolgical Surgery, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kato
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shinya
authors.forename: Kiyomu
authors.initials: K
authors.lastname: Fujii
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohmori
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamashita
mesh_terms: D017209:Apoptosis; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000494:pharmacology / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D005706:Gallbladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000096:biosynthesis; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000494:pharmacology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014746:Vimentin / Q000096:biosynthesis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015820:Cadherins; C469949:GNL3 protein, human; C066855:HGF protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D014746:Vimentin; D051176:beta Catenin; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D019204:GTP-Binding Proteins