Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma
Dual functions of STAT3 in LPS-induced angiogenesis of hepatocellular carcinoma
复制标题
STAT3在LPS诱导的肝细胞癌血管生成中的双重功能
DOI：
10.1016/j.bbamcr.2018.11.016
复制
发表时间：
2019
影响因子：
5.1
通讯作者：
Zhang Hongmin
中科院分区：
文献类型：
--
作者：
Wang Zhuo;Yan Ming;Li Jia'an;Long Jiafu;Li Yan;Zhang Hongmin
肝细胞癌（HCC）是慢性炎症性肝损伤的长期后果。肝损伤与肠屏障缺陷和肝脏暴露于细菌产物（包括脂多糖（LPS））的增加有关，后者可促进肝癌的发生。尽管具有临床意义，但将慢性炎症与HCC发展联系起来的分子介质仍有待阐明。在本研究中，我们探讨了活性信号换能器和转录激活因子3 （STAT3）在lps诱导的HCC血管生成中的重要双重功能。采用血管生成法、ELISA法、共聚焦法、流式细胞术和western blot检测活性STAT3在肿瘤细胞和内皮细胞中的体外效应。在裸鼠异种移植模型中评估其活性STAT3的活性。在这里，我们报告了一种新的机制，通过LPS/STAT3信号促进体外和体内肝癌血管生成。LPS激活STAT3使肿瘤细胞产生血管内皮生长因子（vascular endothelial growth factor， VEGF）， VEGF不仅促进HCC细胞的增殖，还通过STAT3的激活刺激内皮细胞的迁移和成管，从而促进HCC的血管生成。我们的研究结果不仅提供了细菌感染通过促进肝脏血管生成促进肝癌发生的潜在机制，而且考虑到STAT3在血管生成中的双重作用，靶向STAT3可能是HCC治疗的有效治疗策略。
Hepatocellular carcinoma (HCC) is a long-term consequence of chronic inflammatory liver injury. Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products including lipopolysaccharide (LPS), which promotes hepatocarcinogenesis. Despite its clinical significance, the molecular mediator linking chronic inflammation with HCC development remains to be clarified. In this study, we explored the significant dual functions of active signal transducer and activator of transcription 3 (STAT3) in LPS-induced angiogenesis of HCC. Thein vitroeffects of active STAT3 in tumor cells and endothelial cells were assessed using angiogenesis assay, ELISA, confocal assay, flow cytometry and western blot. Thein vivorole of active STAT3 was assessed in xenografts model in nude mice. Here we report a novel mechanism by which LPS/STAT3 signaling promotes the angiogenesis of HCC bothin vitroandin vivo. STAT3 activated by LPS increases the production of vascular endothelial growth factor (VEGF) by tumor cells, which not only promotes the proliferation of HCC cells but also stimulates the migration and tubulogenesis of endothelial cells through STAT3 activation and hence promotes angiogenesis in HCC. Our findings not only provide a potential mechanism by which bacterial infection enhances HCC oncogenesis through promoting the angiogenesis in liver, but also suggest that targeting STAT3 might be an effective therapeutic strategy in HCC treatment considering the dual roles of STAT3 in angiogenesis.