黄芪、莪术配伍对肿瘤相关成纤维细胞介导的肝癌早期转移的调控机制
批准号:
82104408
项目类别:
青年科学基金项目(C类)
资助金额:
30.0 万元
负责人:
张硕
依托单位:
学科分类:
中药药性理论
结题年份:
2024
批准年份:
2021
项目状态:
已结题
项目参与者:
张硕
中文摘要
肿瘤细胞的转移已经成为肿瘤难以治愈的重大问题之一,寻找并阻断肿瘤转移的关键性因素,具有重要的潜在研究价值。既往认为肿瘤的转移属于晚期事件,最近的研究显示:在肿瘤发生的早期阶段,肿瘤相关成纤维细胞就与癌细胞“沆瀣一气”,从原发部位“劫持”癌细胞进行血行扩散。血小板源性生长因子是促进肿瘤相关成纤维细胞介导的早期肿瘤转移的关键因子。针对肝癌走窜难遏之转移特点和气虚血瘀之病机关键,补气活血药黄芪、莪术相使配伍,复本祛邪,补通兼施,共奏抑瘤削结、固摄癌瘤之功。结合本课题组前期研究结果:黄芪、莪术配伍能够诱导人肝癌细胞HepG2凋亡,抑制肝癌血管生成,联合化疗药减少结肠癌的转移。因此本课题组建立肿瘤相关成纤维细胞与肝癌HuH7细胞体外共培养系统和斑马鱼肝癌模型,观察黄芪、莪术配伍对肿瘤相关成纤维细胞介导的肝癌早期阶段的转移情况及分子机制,旨在拓展补气活血药物的临床价值,同时丰富中药配伍理论。
英文摘要
Metastasis of tumor cells has become one of the major problems that are difficult to cure tumors. It is of great potential research value to find and block the key factors of tumor metastasis. Metastasis has been considered a late event. Recent studies have shown that: In the early stages of tumor development, cancer associated fibroblasts (CAFs) associate with the cancer cells, “hijacking” the cancer cells from the primary site to proliferate. Platelet-derived growth factor is a key factor in promoting CAFs -mediated early tumor metastasis. In view of the characteristics of hepatocellular carcinoma metastasis and the pathogenesis of qi deficiency and blood stasis, radix astragali and curcuma were combined to strengthen body resistance and eliminate evil, and to inhibit cancer. Combined with the previous research results of our research group:The combination of radix astragali and curcuma can induce the apoptosis of human hepatocellular carcinoma cells HepG2, inhibit the angiogenesis of hepatocellular carcinoma, and reduce the metastasis of colon cancer. Therefore, our research group established CAFs co-culture system with HuH7 cells in vitro and hepatocellular carcinoma metastasis model in zebrafish. We observed the effect of radix astragali and curcuma on the early stage of CAFs-mediated hepatocellular carcinoma metastasis and its molecular mechanism. The aim of this study was to expand the clinical value of the drugs for invigorating qi and breaking blood and enrich the compatibility theory of traditional Chinese medicine.
尽管目前肝细胞肝癌(hepatocellular carcinoma,HCC)的治疗有了一定的提高,但由于复发导致5年生存率仍低于20%。肿瘤相关成纤维细胞(cancer associated fibroblasts,CAFs)作为肿瘤基质的主要成分,能够分泌趋化因子CCL5和细胞因子IL33促进肝癌转移。本研究建立条件培养基共培养体系和斑马鱼可视化肝癌转移模型,观察黄芪、莪术配伍对CAFs介导的肝癌早期阶段的转移作用及分子机制。结果显示,黄芪、莪术配伍显著抑制CAFs介导的肝癌Huh7细胞增殖和迁移,显著抑制CAFs分泌的CCL5、IL33水平,显著降低CAFs介导的肝癌Huh7细胞中MMP2、MMP9mRNA和蛋白以及CCR5、ST2、p-MEK、p-ERK蛋白的表达。并且在肿瘤转移的早期阶段,黄芪、莪术配伍显著抑制斑马鱼中过表达CCL5或过表达IL33的CAFs介导的肝癌Huh7细胞转移。综上所述,黄芪、莪术配伍能够抑制CAFs介导的肝癌Huh7细胞早期阶段的转移,其机制与抑制CCL5/CCR5/MEK/ERK和IL33/ST2通路有关,为中医药靶向CAFs防治肝癌提供科学依据。
国内基金
海外基金