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Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice

Oncogene volume 33, pages 74–84 (2014)Cite this article

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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.

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Acknowledgements

This work was supported by grants from Grants-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (17590373, 19590432, 20599015 and 23590272), the Takeda Science Foundation and the Public Trust Haraguchi Memorial Cancer Research Fund (to KI-O) and Grants-in-aid for Scientific Research (S) from the Ministry of Education, Science, Technology, Sports, and Culture of Japan (to AY). We greatly thank Dr Jun-ichi Miyazaki (Osaka University) for the gift of the T3b-IL-12 vector, Ms Kozue Takahashi and Mr Takashi Kanna (University of the Ryukyus) for animal care, Dr Atsuo T Sasaki (Harvard University) for help in creating the T3b-cre construction, Dr Richard Blumberg (Harvard Medical School) and Dr Mayu Inaba (University of Michigan) for their constructive discussion and Dr Adrian L Smith (Oxford University) for reading carefully. We also thank Dr Takeshi Arakawa (University of the Ryukyus), Dr Shiki Okamoto, Ms Kumiko Saito (NIPS), Dr Miwa Tamura-Nakano and Dr Takeshi Nitta (NCGM) for steadfast supporting and encouraging us.

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Authors and Affiliations

  1. Molecular Microbiology Group, Center of Molecular Biosciences (COMB), Tropical Biosphere Research Center, University of the Ryukyus, Nishihara, Okinawa, Japan

    K Inagaki-Ohara, H Mayuzumi & G Matsuzaki

  2. Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences (NIPS), Okazaki, Aichi, Japan

    K Inagaki-Ohara & Y Minokoshi

  3. Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine (NCGM), Ichikawa, Chiba, Japan

    K Inagaki-Ohara, T Otsubo, Y I Kawamura & T Dohi

  4. Department of Pathology and Cell Biology Graduate School and Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan

    S Kato

  5. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjyuku, Tokyo, Japan

    A Yoshimura

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  1. K Inagaki-Ohara
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Inagaki-Ohara, K., Mayuzumi, H., Kato, S. et al. Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice. Oncogene 33, 74–84 (2014). https://doi.org/10.1038/onc.2012.540

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