Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment and SUSTech-HKU Joint Laboratories for Matrix Biology and Diseases, Southern University of Science and Technology, Shenzhen 518055, China; State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China; College of Life Sciences, Nankai University, Tianjin 300071, China.
Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment and SUSTech-HKU Joint Laboratories for Matrix Biology and Diseases, Southern University of Science and Technology, Shenzhen 518055, China.
Biochim Biophys Acta Mol Cell Res. 2019 Apr;1866(4):566-574. doi: 10.1016/j.bbamcr.2018.11.016. Epub 2018 Dec 3.
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. The in vitro effects of active STAT3 in tumor cells and endothelial cells were assessed using angiogenesis assay, ELISA, confocal assay, flow cytometry and western blot. The in vivo role 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 both in vitro and in 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.
肝细胞癌 (HCC) 是慢性炎症性肝损伤的长期后果。肝损伤与肠道屏障缺陷和肝脏暴露于细菌产物（包括脂多糖 [LPS]）增加有关，后者促进肝癌发生。尽管其具有临床意义，但将慢性炎症与 HCC 发展联系起来的分子介质仍有待阐明。在这项研究中，我们探讨了活性信号转导和转录激活因子 3 (STAT3) 在 LPS 诱导的 HCC 血管生成中的重要双重作用。使用血管生成测定、ELISA、共聚焦测定、流式细胞术和 Western blot 评估肿瘤细胞和内皮细胞中活性 STAT3 的体外作用。在裸鼠异种移植模型中评估活性 STAT3 的体内作用。在这里，我们报告了一种新的机制，即 LPS/STAT3 信号通过体外和体内促进 HCC 的血管生成。LPS 激活的 STAT3 增加了肿瘤细胞血管内皮生长因子 (VEGF) 的产生，这不仅促进了 HCC 细胞的增殖，而且通过 STAT3 激活刺激内皮细胞的迁移和管腔形成，从而促进 HCC 中的血管生成。我们的发现不仅提供了一种潜在的机制，即细菌感染通过促进肝脏中的血管生成来增强 HCC 致癌作用，而且还表明考虑到 STAT3 在血管生成中的双重作用，靶向 STAT3 可能是 HCC 治疗的一种有效治疗策略。
