Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells.
Cytokine induction of tumor necrosis factor receptor 2 is mediated by STAT3 in colon cancer cells.
复制标题
DOI：
10.1158/1541-7786.mcr-10-0210
复制
发表时间：
2011-12
期刊：
影响因子：
--
通讯作者：
Lund PK
中科院分区：
文献类型：
--
作者：
Hamilton KE;Simmons JG;Ding S;Van Landeghem L;Lund PK
IL-6/STAT 3和TNFα/NFκB通路是炎症相关结肠癌的关键介质。TNFR 2表达在炎症性肠病、结肠炎相关癌症的氧化偶氮甲烷/葡聚糖硫酸钠（AOM/DSS）模型中以及通过IL-6和TNFα的组合而增加。调节TNFR 2的分子机制仍然不确定。本研究使用结肠癌细胞系来检验IL-6和TNFα通过STAT 3和/或NFκB诱导TNFR 2的假设。药理学STAT 3抑制可降低基础和IL-6 + TNFα诱导的TNFR 2。NFκB抑制对IL-6 + TNFα诱导的TNFR 2几乎没有影响，但在单独用TNFα处理的细胞中抑制内源性IL-6和TNFR 2的诱导。染色质免疫沉淀（ChIP）显示IL-6 + TNFα协同诱导STAT 3与TNFR 2启动子中-1578 STAT反应元件结合，但对NFκB与共有位点结合无影响。组成型活性STAT 3足以诱导TNFR 2表达。SOCS 3（一种可减少结肠炎相关癌症临床前模型中肿瘤发生的丝氨酸诱导型STAT 3抑制剂）的过表达降低了丝氨酸诱导的TNFR 2表达和STAT 3与-1578 STAT应答元件的结合。SOCS 3过表达也降低了结肠癌细胞的增殖，并显著降低了结肠癌细胞的锚定非依赖性生长，甚至是过表达TNFR 2的细胞。总之，这些研究表明，IL-6和TNFα诱导的结肠癌细胞中TNFR 2表达主要由STAT 3介导，并提供证据表明TNFR 2可能有助于STAT 3的肿瘤促进作用。
The IL-6/STAT3 and TNFα/NFκB pathways are emerging as critical mediators of inflammation-associated colon cancer. TNFR2 expression is increased in inflammatory bowel diseases, the azoxymethane/dextran sodium sulfate (AOM/DSS) model of colitis-associated cancer, and by combined IL-6 and TNFα. The molecular mechanisms that regulate TNFR2 remain undefined. This study used colon cancer cell lines to test the hypothesis that IL-6 and TNFα induce TNFR2 via STAT3 and/or NFκB. Basal and IL-6 + TNFα-induced TNFR2 were decreased by pharmacological STAT3 inhibition. NFκB inhibition had little effect on IL-6 + TNFα-induced TNFR2, but did inhibit induction of endogenous IL-6 and TNFR2 in cells treated with TNFα alone. Chromatin immunoprecipitation (ChIP) revealed cooperative effects of IL-6 + TNFα to induce STAT3 binding to a -1578 STAT response element in the TNFR2 promoter, but no effect on NFκB binding to consensus sites. Constitutively active STAT3 was sufficient to induce TNFR2 expression. Over-expression of SOCS3, a cytokine-inducible STAT3 inhibitor, which reduces tumorigenesis in preclinical models of colitis-associated cancer, decreased cytokine-induced TNFR2 expression and STAT3 binding to the -1578 STAT response element. SOCS3 over-expression also decreased proliferation of colon cancer cells and dramatically decreased anchorage-independent growth of colon cancer cells, even cells over-expressing TNFR2. Collectively, these studies demonstrate that IL-6 and TNFα-induced TNFR2 expression in colon cancer cells is mediated primarily by STAT3, and provide evidence that TNFR2 may contribute to the tumor-promoting roles of STAT3.