title: IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice.
abstract: Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB 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-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- 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 IFNgamma/STAT1 pathways.
authors.affiliation: Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Hanada
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Chinen
authors.forename: Kazuko
authors.initials: K
authors.lastname: Saeki
authors.forename: Hiromi
authors.initials: H
authors.lastname: Takaki
authors.forename: Keiko
authors.initials: K
authors.lastname: Koga
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Minoda
authors.forename: Takahito
authors.initials: T
authors.lastname: Sanada
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Mimata
authors.forename: Seiya
authors.initials: S
authors.lastname: Kato
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma