IFNγ-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice

Toshikatsu Hanada, Takashi Kobayashi, Takatoshi Chinen, Kazuko Saeki, Hiromi Takaki, Keiko Koga, Yasumasa Minoda, Takahito Sanada, Tomoko Yoshioka, Hiromitsu Mimata, Seiya Kato, Akihiko Yoshimura

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136 Citations (Scopus)

Abstract

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-κB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1-/-Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background, spontaneously developed colorectal carcinomas carrying nuclear β-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)γ-/-SOCS1-/- mice and SOCS1 -/-Tg mice treated with anti-IFNγ antibody did not develop such tumors. STAT3 and NF-κB activation was evident in SOCS1-/-Tg mice, but these were not sufficient for tumor development because these are also activated in IFNγ-/-SOCS1-/- mice. However, colons of SOCS1-/-Tg mice, but not IFNγ-/-SOCS1 -/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNγ/STAT1 pathways. JEM

Original languageEnglish
Pages (from-to)1391-1397
Number of pages7
JournalJournal of Experimental Medicine
Volume203
Issue number6
DOIs
Publication statusPublished - 2006 Jun 12

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Hanada, T., Kobayashi, T., Chinen, T., Saeki, K., Takaki, H., Koga, K., Minoda, Y., Sanada, T., Yoshioka, T., Mimata, H., Kato, S., & Yoshimura, A. (2006). IFNγ-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. Journal of Experimental Medicine, 203(6), 1391-1397. https://doi.org/10.1084/jem.20060436