Schisandrin B downregulates exosomal fibronectin 1 expression to inhibit hepatocellular carcinoma growth

Baoyi Jiang ¹ Jie Yang ¹ Qingtian Huang ^2,3 Wei Li ⁴ Qian Peng ² Huoye Gan ² Tieli Peng ^2* Leyi Yao ^5* Ling Qi ^2,4*

• ¹ Division of Gastroenterology, Institute of Digestive Disease, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
• ² Division of Gastroenterology, Institute of Digestive Disease, the Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China
• ³ Department of Pathology, the Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
• ⁴ Biological Sample Resource Centre, The Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
• ⁵ Zhanjiang Institute of Clinical Medicine，Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, 524033, PR China., Zhanjiang, China

In recent years, natural compounds have attracted wide attention for the treatment of liver cancer.Schisandrin B (Sch B) is a major active constituent of Schisandra chinensis. Our experiments showed that Sch B inhibited the growth of hepatocellular carcinoma (HCC). The tumor-killing effect of drugs is influenced by the tumor microenvironment (TME). In the TME of HCC, macrophages interact with HCC cells and affect its development. We constructed a co-culture system between 2 macrophages and HCC cells and determined that Sch B inhibited HCC cell proliferation. Furthermore, Sch B caused cell cycle arrest, downregulated the expression of CDK4, CDK2, and cyclin A2 proteins, upregulated the expression of p27 Kip1 protein, and blocked HCC cells in the S phase. Additionally, Sch B inhibited the migration of HCC cells in a co-culture system. Exosomes are important mediators of cellular interactions in the TME. We further collected exosomes from the co-culture system for identification and performed proteomic analysis, and determined that Sch B downregulated the expression of fibronectin 1 (FN1) protein in exosomes in the co-culture system. In vivo, Sch B inhibited the growth of HCC tumors and downregulated the expression of FN1 protein in tumor tissues. In general, Sch B may inhibit the development of HCC by inhibiting the expression of exosomal FN1during interactions between macrophages and HCC cells.