title: Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice.
abstract: Leptin acts on its receptor (ObR) in the hypothalamus to inhibit food intake and energy expenditure. Leptin and ObR are also expressed in the gastrointestinal tract; however, the physiological significance of leptin signaling in the gut remains uncertain. Suppressor of cytokine signaling 3 (SOCS3) is a key negative feedback regulator of ObR-mediated signaling in the hypothalamus. We now show that gastrointestinal epithelial cell-specific SOCS3 conditional knockout (T3b-SOCS3 cKO) mice developed gastric tumors by enhancing leptin production and the ObRb/signal transducer and activator of transcription 3 (STAT3) signaling pathway. All T3b-SOCS3 cKO mice developed tumors in the stomach but not in the bowels by 2 months of age, even though the SOCS3 deletion occurred in both the epithelium of stomach and bowels. The tumors developed in the absence of the inflammatory response and all cKO mice died within 6 months. These tumors displayed pathology and molecular alterations, such as an increase in MUC2 (Mucin 2, oligomeric mucus/gel-forming) and TFF3 (trefoil factor 3), resembling human intestinal-type gastric tumors. Administration of antileptin antibody to T3b-SOCS3 cKO mice reduced hyperplasia of gastric mucosa, which is the step of the initiation of gastric tumor. These data suggest that SOCS3 is an antigastric tumor gene that suppresses leptin overexpression and ObRb/STAT3 hyperactivation, supporting the hypothesis that the leptin/ObRb/STAT3 axis accelerates tumorigenesis and that it may represent a new therapeutic target for the treatment of gastric cancer.
authors.affiliation: 1] Molecular Microbiology Group, Center of Molecular Biosciences (COMB), Tropical Biosphere Research Center, University of the Ryukyus, Nishihara, Okinawa, Japan [2] Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), Okazaki, Aichi, Japan [3] Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine (NCGM), Ichikawa, Chiba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Inagaki-Ohara
authors.affiliation: Molecular Microbiology Group, Center of Molecular Biosciences (COMB), Tropical Biosphere Research Center, University of the Ryukyus, Nishihara, Okinawa, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Mayuzumi
authors.affiliation: Department of Pathology and Cell Biology Graduate School and Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.affiliation: Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), Okazaki, Aichi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Minokoshi
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine (NCGM), Ichikawa, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Otsubo
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine (NCGM), Ichikawa, Chiba, Japan.
authors.forename: Y I
authors.initials: YI
authors.lastname: Kawamura
authors.affiliation: Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine (NCGM), Ichikawa, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Dohi
authors.affiliation: Molecular Microbiology Group, Center of Molecular Biosciences (COMB), Tropical Biosphere Research Center, University of the Ryukyus, Nishihara, Okinawa, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Matsuzaki
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjyuku, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D063646:Carcinogenesis / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000378:metabolism; D020738:Leptin / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C515447:leptin receptor, mouse; D011494:Protein Kinases; C065999:Sp1 kinase