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

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 beta-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.