STAT2 contributes to promotion of colorectal and skin carcinogenesis.
STAT2 contributes to promotion of colorectal and skin carcinogenesis.
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DOI：
10.1158/1940-6207.capr-09-0105
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Colburn NH
中科院分区：
文献类型：
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作者：
Gamero AM;Young MR;Mentor-Marcel R;Bobe G;Scarzello AJ;Wise J;Colburn NH
STAT2是I型干扰素（IFN-α/β）信号转导通路中必需的转录因子，因其介导抗病毒免疫和细胞生长抑制而闻名。与STAT家族的其他成员不同，ifn是迄今为止已知的唯一可以激活STAT2的细胞因子。鉴于ifn具有炎症和抗增殖的双重性质，我们假设STAT2通过改变炎症免疫反应来阻止炎症诱导的结直肠癌和皮肤癌的发生。与我们的假设相反，通过延长生存期、降低腺瘤发生率、缩小息肉和减少慢性炎症来衡量，STAT2的缺失抑制了AOM/ dss诱导的结直肠癌的发生。STAT2缺乏还可以抑制DMBA/ tpa诱导的皮肤癌，这可以通过减少乳头瘤的多样性来证明。STAT2促进癌变的潜在机制是通过激活促炎介质。STAT2的缺失减少了AOM/ dss诱导的促炎介质如白细胞介素6和CCL2的表达和释放，减少了皮肤癌细胞中白细胞介素6的释放，从而降低了STAT3的激活。我们的研究发现，STAT2是结直肠癌和皮肤癌变的一个新因素，它可能会增加促炎介质的基因表达和分泌，进而激活致癌的STAT3信号通路。
STAT2 is an essential transcription factor in the type I interferon (IFN-α/β) signal transduction pathway and known for its role in mediating antiviral immunity and cell growth inhibition. Unlike other members of the STAT family, IFNs are the only cytokines known to date that can activate STAT2. Given the inflammatory and antiproliferative dual nature of IFNs, we hypothesized that STAT2 prevents inflammation-induced colorectal and skin carcinogenesis by altering the inflammatory immune response. Contrary to our hypothesis, deletion of STAT2 inhibited AOM/DSS-induced colorectal carcinogenesis as measured by prolonged survival, lower adenoma incidence, smaller polyps, and less chronic inflammation. STAT2 deficiency also inhibited DMBA/TPA-induced skin carcinogenesis as indicated by reduced papilloma multiplicity. A potential mechanism by which STAT2 promotes carcinogenesis is through activation of pro-inflammatory mediators. Deletion of STAT2 decreased AOM/DSS-induced expression and release of pro-inflammatory mediators such as interleukin 6 and CCL2 and decreased interleukin-6 release from skin carcinoma cells, which then decreased STAT3 activation. Our findings identify STAT2 as a novel contributor to colorectal and skin carcinogenesis that may act to increase the gene expression and secretion of pro-inflammatory mediators, which in turn activate the oncogenic STAT3 signaling pathway.