Biejiajian pill inhibits progression of hepatocellular carcinoma by downregulating PDGFRO signaling in cancer-associated fibroblasts

作者：Chen, Weicong; Yang, Xuemei; Sun, Jialing; Chen, Yuyao; Zhao, Wenting; He, Chunyu; An, Haiyan; Pang, Jie; Xu, Wei; Wen, Bin^*; Sun, Haitao^*; He, Songqi^*

来源：Journal of Ethnopharmacology, 2023, 301: 115825.

DOI：10.1016/j.jep.2022.115825

• Biejiajian pill
• Hepatocellular carcinoma
• Cancer-associated fibroblasts
• Platelet-derived growth factor receptor beta

Ethnopharmacological relevance: Biejiajian pill (BJJP) is a canonical formula that is clinically used to treat chronic liver disease, especially to decrease the incidence of hepatocellular carcinoma (HCC). However, the mechanisms underlying the prevention of HCC progression by BJJP remain unclear.Aim of the study: This study aimed to determine whether BJJP inhibits HCC progression by downregulating platelet-derived growth factor receptor beta (PDGFRO) signaling in cancer-associated fibroblasts (CAFs) in a mouse model of diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced HCC.Materials and methods: C57BL/6 male mice were intraperitoneally injected with DEN 2 weeks after birth, followed by repeated injections of CCl4 weekly from 6 weeks of age onwards, to recapitulate features of HCC. At week 14, BJJP was orally administered to mice. The effects of BJJP on HCC progression were evaluated using histology, immunohistochemistry, and serum biochemical marker levels. Transcriptome analysis, molecular docking, quantitative real-time PCR, and Western blot were used to study the genes targeted by BJJP and the associated signaling pathway. The effects of BJJP on PDGFRO signaling in CAFs and the underlying mechanism were demonstrated.Results: BJJP treatment significantly suppressed carcinogenesis and cancer progression, and it ameliorated liver inflammation in mice with HCC. A total of 176 genes, including PDGFRO, were significantly downregulated after BJJP treatment and five components of BJJP with high binding affinity to PDGFRO were identified. BJJP inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK3O) by suppressing PDGFRO expression in CAFs, and it also downregulated the expression of the downstream proteins hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A). Furthermore, BJJP-containing serum consistently reduced PDGFRO, HGF, and VEGF-A expression levels in HSC-derived CAFs in vitro. Importantly, PDGF-BB induced PDGFRO activation in CAFs and both BJJP and sunitinib (a kinase inhibitor) inhibited PDGF-BB/PDGFRO signaling.Conclusion: BJJP inhibits the progression of HCC through suppressing VEGF-A and HGF expression in CAFs by downregulating PDGFRO signaling.

• 单位
  广州中医药大学; 南方医科大学