Oroxylin A Inhibits Colitis-associated Carcinogenesis Through Modulating the IL-6/STAT3 Signaling Pathway
Oroxylin A Inhibits Colitis-associated Carcinogenesis Through Modulating the IL-6/STAT3 Signaling Pathway
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Oroxylin A 通过调节 IL-6/STAT3 信号通路抑制结肠炎相关的癌变
DOI：
10.1097/mib.0b013e318293c5e0
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发表时间：
2013-08-01
影响因子：
4.9
通讯作者：
Hu, Rong
中科院分区：
文献类型：
--
作者：
Yang, Xi;Zhang, Fengyi;Hu, Rong
背景：炎症性肠病（包括溃疡性结肠炎和克罗恩病）患者发生结直肠癌的风险显著增加，炎症性肠病和炎症相关性胃肠癌均存在异常的白细胞介素（IL）-6/STAT3信号通路。我们先前已经发现，在人结肠肿瘤HCT-116细胞中，oroxylin A抑制NF-B信号传导。方法：用不同浓度的木脂素A处理HCT-116细胞，观察不同浓度的木脂素A对HCT-116细胞增殖的影响。Western blot和免疫荧光法检测IL-6/STAT 3信号通路相关蛋白的表达。在C57 BL/6小鼠中，通过用10 mg/kg氧化偶氮甲烷（AOM）随后用3个周期的2.5%葡聚糖硫酸钠的组合治疗来诱导结肠炎相关结肠直肠癌的小鼠模型。实时荧光定量PCR检测IL-6和IL-1基因表达。结果：Oroxylin A能有效抑制人HCT-116细胞IL-6/STAT 3信号通路，且该作用是可逆的。在整个实验期间，膳食给予乳清素A显著降低了结肠癌的肿瘤负荷，抑制了细胞增殖，并诱导了细胞凋亡。在经oroxylin A处理的小鼠中，炎性细胞因子IL-6和IL-1的表达在肿瘤中降低。结论：在AOM/葡聚糖硫酸钠小鼠模型和HCT-116细胞中，Oroxylin A通过调节IL-6/STAT 3信号通路抑制结肠炎相关的癌变。
Background:Patients with inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, are at a significantly increased risk of developing colorectal cancer, and aberrant interleukin (IL)-6/STAT3 signaling pathway exists in both inflammatory bowel disease and inflammation-related gastrointestinal cancers. We have previously found that oroxylin A inhibited the NF-B signaling in human colon tumor HCT-116 cells. However, whether oroxylin A could inhibit the colitis-associated carcinogenesis remains to be determined.Methods:HCT-116 cells were treated with various concentrations of oroxylin A. Expression of relative proteins of IL-6/STAT3 signaling pathway was assayed by Western blot and immunofluorescence analysis. Mouse model for colitis-associated colorectal cancer was induced by a combined treatment with 10 mg/kg azoxymethane (AOM) followed by 3 cycles of 2.5% dextran sodium sulfate in C57BL/6 mice. IL-6 and IL-1 gene expression were analyzed by quantitative real-time PCR. Expression of relative proteins was examined by immunohistochemistry and Western blot.Results:Oroxylin A effectively inhibited IL-6/STAT3 pathway in human HCT-116 cells, and the effect of oroxylin A was reversible. Dietary administration of oroxylin A throughout the experimental period significantly reduced the tumor burden, inhibited cell proliferation, and induced apoptosis in colon carcinomas. The expression of inflammatory cytokines IL-6 and IL-1 decreased in tumors in oroxylin A-treated mice. The IL-6/STAT3 signaling pathway was attenuated in oroxylin A-treated mice.Conclusions:Our results demonstrated that oroxylin A inhibits colitis-associated carcinogenesis through modulating IL-6/STAT3 pathway in AOM/dextran sodium sulfate mouse model and in HCT-116 cells.