title: ASPP2 suppresses invasion and TGF-β1-induced epithelial-mesenchymal transition by inhibiting Smad7 degradation mediated by E3 ubiquitin ligase ITCH in gastric cancer.
abstract: ASPP2 regulates cell polarity and cell-cell adhesion by binding to, and co-localizing with PAR3 at tight junctions. Here we show a novel role of ASPP2 in suppressing gastric cancer (GC) invasiveness. Immunoprecipitation and immunofluorescence analyses showed that ASPP2 promoted the recruitment of PAR3 to cell-cell junctions in GC cells. Diminished expression of ASPP2 and loss of junctional PAR3 localization were significantly associated with diffuse-type histology, deeper invasion depth, positive peritoneal dissemination and worse prognosis in primary GC. ASPP2 suppressed migration and invasion of GC cells in vitro and peritoneal dissemination of GC cells in vivo in a mouse model. ASPP2 suppressed epithelial-mesenchymal transition (EMT) induced by TGF-β1-Smad2/3 signaling in GC cells through suppression of the degradation of Smad7, a negative regulator of TGF-β1-Smad2/3 signaling, by interacting with the E3 ubiquitin ligase ITCH. In conclusion, ASPP2 suppresses invasion, peritoneal dissemination and TGF-β1-induced EMT by inhibiting Smad7 degradation mediated by ITCH.
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Molecular Cytogenetics, Medical Research Institute and Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Gen
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: yasuik@koto.kpu-m.ac.jp.
authors.forename: Kohichiroh
authors.initials: K
authors.lastname: Yasui
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kitaichi
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Iwai
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Terasaki
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Dohi
authors.affiliation: Department of Gastroenterology and Hepatology, North Medical Center Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Gastroenterology and Hepatology, North Medical Center Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Department of Gastroenterology and Hepatology, North Medical Center Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inada
authors.affiliation: Department of Gastroenterology and Hepatology, North Medical Center Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Fukui
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masayasu
authors.initials: M
authors.lastname: Jo
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Michihisa
authors.initials: M
authors.lastname: Moriguchi
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Taichiro
authors.initials: T
authors.lastname: Nishikawa
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Atushi
authors.initials: A
authors.lastname: Umemura
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konishi
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010534:Peritoneal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D055550:Protein Stability; D059748:Proteolysis; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; D012097:Repressor Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; C508960:TGFB1 protein, human; C090468:TP53BP2 protein, human; D053773:Transforming Growth Factor beta1; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ASPP2; Epithelial–mesenchymal transition; Gastric cancer; ITCH; Smad7; TGF-β1