A requirement of STAT3 DNA binding precludes Th-1 immunostimulatory gene expression by NF-κB in tumors.
A requirement of STAT3 DNA binding precludes Th-1 immunostimulatory gene expression by NF-κB in tumors.
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DOI：
10.1158/0008-5472.can-10-3304
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发表时间：
2011-06-01
期刊：
影响因子：
11.2
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Lee H;Deng J;Xin H;Liu Y;Pardoll D;Yu H
STAT 3和NF-κB在多种癌症中被持续激活，通过多个共同基因的转录激活促进肿瘤细胞增殖、存活、血管生成和转移。特别地，尽管肿瘤中NF-κB水平升高，STAT 3也抑制参与先天性和适应性抗肿瘤免疫的许多NF-κ B诱导基因。在这里，我们表明，许多NF-κB下游靶基因在肿瘤中的表达依赖于STAT 3 DNA结合。当STAT 3在肿瘤细胞和肿瘤浸润免疫细胞中升高时，持续活化的NF-κB与STAT 3相互作用，并优先结合启动子中具有STAT 3结合位点的基因。大量与肿瘤发生和慢性炎症相关的NF-κB下游基因含有STAT 3 DNA结合位点。相反，许多与抗肿瘤免疫相关的基因缺乏STAT 3 DNA结合位点，并且当肿瘤中STAT 3被抑制时，只能被NF-κB激活。通过在免疫刺激基因启动子中的位点特异性诱变引入STAT 3 DNA结合序列允许其在肿瘤细胞中被NF-κB转录激活。此外，STAT 3促进NF-κB与对肿瘤生长重要的基因结合，同时抑制其与生长中的肿瘤（包括肿瘤浸润性免疫细胞）中的Th-1免疫刺激基因结合。我们的研究结果提供了一些致癌/炎症和Th-1免疫刺激基因在癌症中的差异调节。
Both STAT3 and NF-κB are persistently activated in diverse cancers, promoting tumor cell proliferation, survival, angiogenesis and metastasis through transcriptional activation of multiple common genes. Paradoxically, STAT3 also suppresses many NF-κB-inducible genes involved in innate and adaptive anti-tumor immunity despite an elevated level of NF-κB in tumors. Here we show that expression of many NF-κB downstream target genes in tumors depends on STAT3 DNA-binding. When STAT3 is elevated in tumor cells and tumor-infiltrating immune cells, persistently activated NF-κB interacts with STAT3 and preferentially binds to genes with STAT3-binding site(s) in the promoters. A large number of NF-κB downstream genes associated with oncogenesis and chronic inflammation contain STAT3 DNA-binding site(s). In contrast, many genes frequently associated with anti-tumor immunity lack STAT3 DNA-binding site(s) and can only be activated by NF-κB when STAT3 is inhibited in tumors. Introducing STAT3 DNA-binding sequences by site-specific mutagenesis in an immunostimulatory gene promoter allows its transcriptional activation by NF-κB in tumor cells. Furthermore, STAT3 facilitates NF-κB binding to genes important for tumor growth while inhibiting its binding to Th-1 immunostimulatory genes in growing tumors including tumor-infiltrating immune cells. Our results provide insight into how some of the oncogenic/inflammatory and Th-1 immunostimulatory genes are differentially regulated in cancer.