IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice.
IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice.
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Ifngamma依赖性的，在SOCS1缺陷小鼠中大肠癌的自发发展。
DOI：
10.1084/jem.20060436
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发表时间：
2006-06-12
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据估计，大约20%的人类癌症是由慢性炎症发展而来的。近年来，NF-κB通路在炎症相关性肿瘤的发生发展中起着重要作用，但JAK/STAT通路作为促炎细胞因子的另一重要信号通路，其作用仍有待进一步研究。细胞因子信号转导抑制因子-1（SOCS 1）是细胞因子应答的重要生理调节因子，在多种人类癌症中发现了SOCS 1基因通过DNA甲基化而沉默。在这里，我们证明了SOCS 1缺陷小鼠（SOCS 1 −/−Tg小鼠），其中SOCS 1表达在SOCS 1 −/−背景下的T和B细胞中恢复，在6个月大时自发发展携带核β-连环蛋白积累和p53突变的结直肠癌。然而，干扰素（IFN）γ−/− SOCS 1 −/−小鼠和用抗IFN γ抗体处理的SOCS 1 −/−Tg小鼠未发生此类肿瘤。STAT 3和NF-κB活化在SOCS 1 −/−Tg小鼠中是明显的，但这些对于肿瘤发展是不够的，因为它们在IFNγ−/− SOCS 1 −/−小鼠中也被活化。然而，SOCS 1 −/−Tg小鼠的结肠，而不是IFNγ−/− SOCS 1 −/−小鼠的结肠，显示出STAT 1的过度活化，这导致了致癌相关酶，环氧合酶-2和诱导型一氧化氮合酶的诱导。这些数据有力地表明，SOCS 1是一种独特的抗癌基因，通过调节IFNγ/STAT 1通路来防止慢性炎症介导的致癌作用。
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.