五味子乙素下调外泌体纤连蛋白1表达以抑制肝细胞癌生长。
Schisandrin B downregulates exosomal fibronectin 1 expression to inhibit hepatocellular carcinoma growth.
作者信息
Jiang Baoyi, Yang Jie, Huang Qingtian, Li Wei, Peng Qian, Gan Huoye, Peng Tieli, Yao Leyi, Qi Ling
机构信息
Division of Gastroenterology, Institute of Digestive Disease, The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guang Dong, China.
Department of Pathology, The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guang Dong, China.
出版信息
Front Pharmacol. 2025 Mar 28;16:1547685. doi: 10.3389/fphar.2025.1547685. eCollection 2025.
INTRODUCTION
In recent years, natural compounds have attracted wide attention for the treatment of liver cancer due to their therapeutic potential and reduced toxicity. Among these, Schisandrin B (Sch B), a primary bioactive component derived from Schisandra chinensis, has shown notable antitumor activity; however, its specific mechanism remains unclear.
METHODS
The effect of Sch B on the growth of hepatocellular carcinoma(HCC) cells were assessed using CCK-8 assay, colony formation assay and EdU assay, and apoptosis was detected by flow cytometry. The co-culture system of macrophages and HCC cells was established to detect the effect of Sch B on the cell viability and cell cycle changes of HCC cells in the co-culture system. Then, the migration of HCC cells in the co-culture system was studied using a subtoxic concentration of Sch B. Exosomes of the co-culture system with or without Sch B effect were collected for identification and protein spectrum analysis. The differential protein was analyzed by KEGG enrichment analysis and protein interaction network, which was verified by western blotting. Meanwhile, the expression changes of macrophage polarization markers were detected. Finally, the inhibitory effect of Sch B on HCC and the changes of FN1 were verified by in vivo experiments.
RESULTS
Sch B inhibited HCC cell growth; moreover, it significantly suppressed HCC cell proliferation in the co-culture system and induced S-phase cell cycle arrest by downregulating CDK4, CDK2, and cyclin A2 while upregulating p27 Kip1. Additionally, Sch B inhibited the migration of HCC cells in the co-culture system.The differentially expressed protein fibronectin 1(FN1) in liver cancer patients was higher than that in healthy people. Moreover, after SchB treatment, the expression of FN1 protein in exosomes decreased and the macrophages exhibited M1 polarization. In vivo experiments also verified that Sch B inhibited HCC growth and downregulated the expression of FN1 protein in tumor tissues.
CONCLUSION
Sch B may inhibit the development of HCC by inhibiting the expression of exosomal FN1during interactions between macrophages and HCC cells.
引言
近年来，天然化合物因其治疗潜力和较低的毒性在肝癌治疗方面引起了广泛关注。其中，五味子乙素（Sch B）是从五味子中提取的一种主要生物活性成分，已显示出显著的抗肿瘤活性；然而，其具体机制仍不清楚。
方法
采用CCK-8法、集落形成试验和EdU试验评估Sch B对肝癌（HCC）细胞生长的影响，通过流式细胞术检测细胞凋亡。建立巨噬细胞与HCC细胞的共培养体系，以检测Sch B对共培养体系中HCC细胞活力和细胞周期变化的影响。然后，使用亚毒性浓度的Sch B研究共培养体系中HCC细胞的迁移情况。收集有或无Sch B作用的共培养体系的外泌体进行鉴定和蛋白质谱分析。通过KEGG富集分析和蛋白质相互作用网络对差异蛋白进行分析，并通过蛋白质免疫印迹法进行验证。同时，检测巨噬细胞极化标志物的表达变化。最后，通过体内实验验证Sch B对肝癌的抑制作用及FN1的变化。
结果
Sch B抑制HCC细胞生长；此外，它在共培养体系中显著抑制HCC细胞增殖，并通过下调CDK4、CDK2和细胞周期蛋白A2，同时上调p27 Kip1诱导S期细胞周期阻滞。此外，Sch B抑制共培养体系中HCC细胞的迁移。肝癌患者中差异表达的蛋白纤连蛋白1（FN1）高于健康人。此外，Sch B处理后，外泌体中FN1蛋白的表达降低，巨噬细胞呈现M1极化。体内实验也证实Sch B抑制HCC生长并下调肿瘤组织中FN1蛋白的表达。
结论
Sch B可能通过抑制巨噬细胞与HCC细胞相互作用过程中外泌体FN1的表达来抑制肝癌的发展。
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