Abstract
Objective:Ginsenoside Rh1(G-Rh1)has been confirmed to inhibit the growth of breast cancer and colon cancer,but its therapeutic effect on hepatocellular carcinoma(HCC)is unclear.This study investigates the therapeutic effect of G-Rh1 on HCC as well as the underlying mechanism.Methods:Bioinformatics methods were used to analyze glucocorticoid receptor(GR)expression and the tumor microenvironment in HCC tissues from HCC patients.The effect of G-Rh1 on HCC cells was inves-tigated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method.The therapeutic effect of G-Rh1 was investigated in vivo using subcutaneous transplantation models in C57BL/6J and nude mice.Additionally,the proportion of infiltrating immune cells in tumors was analyzed using flow cytometry,the GR and major histocompatibility complex class-I(MHC-I)expression of HCC cells after G-Rh1 treatment was analyzed using Western blotting,and G-Rh1-treated Hepa1-6 cells were cocultured with bone marrow-derived dendritic cells and B3Z T cells to further analyze the ability of G-Rh1 to induce dendritic cell(DC)maturation and CD8+T cell activation.Results:GR expression was upregulated in HCC tissues,and high GR expression was associated with a worsened immune microenvironment.In vitro studies showed that G-Rh1 had no significant effect on the proliferation of HCC cells,while in vivo studies showed that G-Rh1 exerted antitumor effects in C57BL/6J mice but not in nude mice.Further research revealed that G-Rh1 ameliorated the immunosup-pressive tumor microenvironment,thereby enhancing the antitumor effects of lenvatinib by increasing the infiltration of CD8+T cells,mature DCs,and MHC-I-positive cells.MHC-I was upregulated by G-Rh1 via GR suppression.Moreover,overexpression of GR abolished the G-Rh1-mediated promotion of MHC-I expression in Huh7 cells,as well as the maturation of DCs and the activation of CD8+T cells.Conclusion:G-Rh1 can regulate the immune microenvironment of HCC by targeting GR,thus increasing the antitumor effect of lenvatinib.
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