The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 22 May 2006 doi:10.1084/jem.20060436
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 6, 1391-1397
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BRIEF DEFINITIVE REPORT

 IFN{gamma}-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice

Toshikatsu Hanada1,2, Takashi Kobayashi1, Takatoshi Chinen1, Kazuko Saeki1, Hiromi Takaki1, Keiko Koga1, Yasumasa Minoda1, Takahito Sanada1, Tomoko Yoshioka1, Hiromitsu Mimata2, Seiya Kato3, and Akihiko Yoshimura1

1 Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
2 Department of Oncological Science (Urology), Oita University, Oita 879-5593, Japan
3 Department of Pathology, Kurume University, Kurume 830-0011, Japan

CORRESPONDENCE Akihiko Yoshimura: yakihiko{at}bioreg.kyushu-u.ac.jp

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-{kappa}B 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 ß-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN){gamma}–/–SOCS1–/– mice and SOCS1–/–Tg mice treated with anti-IFN{gamma} antibody did not develop such tumors. STAT3 and NF-{kappa}B activation was evident in SOCS1–/–Tg mice, but these were not sufficient for tumor development because these are also activated in IFN{gamma}–/–SOCS1–/– mice. However, colons of SOCS1–/–Tg mice, but not IFN{gamma}–/–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 IFN{gamma}/STAT1 pathways.

T. Hanada and T. Kobayashi contributed equally to this work.


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