IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer
IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer
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DOI：
10.1007/s13277-015-4372-4
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发表时间：
2016-04-01
期刊：
影响因子：
--
通讯作者：
Yang, Hui
中科院分区：
文献类型：
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作者：
Wu, Xiaoqin;Yang, Tao;Yang, Hui
胃癌是世界上第二大常见恶性肿瘤，是全球健康的主要威胁。IL-17是一种CD 4 T细胞衍生的血管生成介质，通过调节多种促血管生成因子（包括血管内皮生长因子（VEGF））的产生，在刺激血管生成中发挥重要作用。胃癌组织中VEGF的表达水平与肿瘤的进展和转移有关。信号转导子和转录激活子3（Stat 3）的异常激活使肿瘤细胞高度血管生成，其表现为微血管密度（MVD）增加，被认为是胃癌血管生成不良预后的潜在分子标志。我们确定IL-17 A通过Stat 3介导的信号通路诱导VEGF上调和新生血管形成，并假设通过使用磷酸化Stat 3的抑制剂JSI-124阻断Stat 3活化可以显著降低VEGF表达，从而可以预防血管生成。我们在动物模型中的细胞和异种移植物中用IL-17 A处理JSI-124时，显示出血管生成和肿瘤进展的抑制，并表明用JSI-124靶向Stat通路可以衍生出胃癌的有效治疗靶点，并且可能是胃癌治疗中有前途的药物。
Gastric cancer is the world's second most common malignancy and is a major threat to global health. IL-17, a CD4 T cell-derived mediator of angiogenesis, plays a major role in stimulating angiogenesis by regulating the production of a variety of proangiogenic factors, including the vascular endothelial growth factor (VEGF). The level of VEGF expression correlates with tumor progression and metastasis in gastric cancer tissues. Abnormal activation of signal transducer and activator of transcription 3 (Stat3) rendered the tumor cells highly angiogenic, which is manifested by an increased microvascular density (MVD) and considered it as a potential molecular marker for poor prognosis in gastric cancer angiogenesis. We determined that IL-17A-induced VEGF upregulation and neovascularization through a Stat3-mediated signaling pathway and hypothesized that blocking the Stat3 activation by using JSI-124, an inhibitor of phosphorylated Stat3, could significantly reduce the VEGF expression and can thus prevent angiogenesis. We showed an inhibition of angiogenesis and tumor progression when JSI-124 was treated with IL-17A in the cells and xenografts in an animal model and suggested that targeting the Stat pathway with JSI-124 could derive an effective therapeutic target for gastric cancers and could be a promising drug in gastric cancer treatment.