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

K. Inagaki-Ohara, H. Mayuzumi, S. Kato, Y. Minokoshi, T. Otsubo, Y. I. Kawamura, T. Dohi, G. Matsuzaki, A. Yoshimura

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32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)74-84
Number of pages11
JournalOncogene
Volume33
Issue number1
DOIs
Publication statusPublished - 2014 Jan 2

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Keywords

  • SOCS3
  • gastric tumor
  • leptin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Inagaki-Ohara, K., Mayuzumi, H., Kato, S., Minokoshi, Y., Otsubo, T., Kawamura, Y. I., Dohi, T., Matsuzaki, G., & Yoshimura, A. (2014). Enhancement of leptin receptor signaling by SOCS3 deficiency induces development of gastric tumors in mice. Oncogene, 33(1), 74-84. https://doi.org/10.1038/onc.2012.540