An Integrative Analysis Reveals the Potential Mechanism between Herbal Medicine Yinchen and Immunoregulation in Hepatocellular Carcinoma

Abstract

Aims. Abundant evidences in traditional Chinese medicine (TCM) supported the therapeutic value of herbal medicine Yinchen in hepatocellular carcinoma (HCC), but the underlying mechanism remains to be investigated. Main Methods. The intersection of immune gene set, module genes, HCC-associated genes, and target genes of Yinchen was employed for further analyses. The module genes were identified by weighted gene coexpression network analysis, and the other three gene sets were obtained from public databases. Subsequently, we further explored the clinical value and immunoregulation of the hub gene of intersection. The relevant pathways related to hub gene expression were investigated by gene set enrichment analysis. Finally, the interaction of active compounds and target genes was validated by molecular docking. Key Findings. Thirteen active compounds and 90 target genes of Yinchen were included. After constructing the network among Yinchen, target genes, and HCC, BIRC5 was identified as the hub gene. Significant difference was found between the high-expressed group and the low-expressed group in survival and stage. Different immune subtypes also presented significant difference in BIRC5 expression. Moreover, NK cell and T cell (CD4+ effector memory and CD4+ memory resting) were negatively correlated with BIRC5 expression, while CTLA4 and LAG3 were positively correlated. The results of molecular docking further validated a good binding activity of quercetin-BIRC5 interaction. Significance. In summary, our research identified for the first time a novel underlying association among herbal medicine Yinchen, BIRC5, immunotherapy, and HCC. We speculated that Yinchen may target the immune checkpoints (CTLA4 and LAG3) and activate the immune cells by suppressing BIRC5.

Exosome CTLA-4 Regulates PTEN/CD44 Signal Pathway in Spleen Deficiency Internal Environment to Promote Invasion and Metastasis of Hepatocellular Carcinoma

“…Clinical evidence has shown that anti–CTLA-4 therapy can enhance the activation of effector T cells ( Maker et al, 2005 ), increase the ratio of effector T cells to Treg ( Quezada et al, 2006 ; Curran et al, 2010 ; Ou et al, 2018 ), and promote the transport of activated T cells to tumor tissues ( Quezada et al, 2006 ). Our previous study found that traditional Chinese medicine could improve the tumor microenvironment of patients to treat liver cancer and speculated that the immune checkpoints CTLA-4, LAG-3, and BIRC5 are the key targets for activating immune cells to treat liver cancer ( Mo et al, 2020 ). However, only a minority of people can respond to immunotherapy ( Mahoney et al, 2015 ).…”

The Use of Phytochemicals to Improve the Efficacy of Immune Checkpoint Inhibitors: Opportunities and Challenges

“…The recently conducted phytochemical analysis of Artemisia annua L. demonstrated the presence of several flavonoids, hydroxycoumarins, and phytosterols, phytochemicals with possible anticancer effects on immune checkpoints [113]. Furthermore, recent gene expression analyses in HCC about Artemisia scoparia demonstrated the increased expression of BIRC5 and secondary expression of CTLA-4 and LAG-3 immune checkpoints and a possible immune activation with this herbal medicine [114]. Further studies evaluating the phytochemical constituent of herbal medications and corresponding effects on the immune checkpoints are needed.…”

Integrating single-cell and spatial transcriptomics to elucidate the crosstalk between cancer-associated fibroblasts and cancer cells in hepatocellular carcinoma with spleen-deficiency syndrome

“… 5 , 6 Meanwhile, data from both laboratory and clinical studies tend to support the notion that Chinese herbal medicine can ameliorate the and limit HCC progression by improving the pre-tumorigenic microenvironment. 7 , 8 However, the underlying mechanism by which SDS regulates HCC progression remains to be explored.…”