Construction of a Prognostic Model for Hepatocellular Carcinoma Based on Macrophage Polarization-Related Genes

Han Chen,1,2 Jianhao Li,1,2 Dan Cao,1,2 Hong Tang1,2 1Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China; 2Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Hong Tang, Email tanghong6198@wchscu.cnBackground: The progression of hepatocellular carcinoma (HCC) is related to macrophage polarization (MP). Our aim was to identify genes associated with MP in HCC patients and develop a prognostic model based on these genes.Results: We successfully developed a prognostic model consisting of six MP-related genes (SCN4A, EBF3, ADGRB2, HOXD9, CLEC1B, and MSC) to calculate the risk score for each patient. Patients were then classified into high- and low-risk groups based on their median risk score. The performance of the MP-related prognostic model was evaluated using Kaplan-Meier and ROC curves, which yielded favorable results. Additionally, the nomogram demonstrated good clinical effectiveness and displayed consistent survival predictions with actual observations. Gene Set Enrichment Analysis (GSEA) revealed enrichment of pathways related to KRAS signaling downregulation, the G2M checkpoint, and E2F targets in the high-risk group. Conversely, pathways associated with fatty acid metabolism, xenobiotic metabolism, bile acid metabolism, and adipogenesis were enriched in the low-risk group. The risk score positively correlated with the number of invasion-related genes. Immune checkpoint expression differed significantly between the two groups. Patients in the high-risk group exhibited increased sensitivity to mitomycin C, cisplatin, gemcitabine, rapamycin, and paclitaxel, while those in the low-risk group showed heightened sensitivity to doxorubicin. These findings suggest that the high-risk group may have more invasive HCC with greater susceptibility to specific drugs. IHC staining revealed higher expression levels of SCN4A in HCC tissues. Furthermore, experiments conducted on HepG2 cells demonstrated that supernatants from cells with reduced SCN4A expression promoted M2 macrophage polarization marker, CD163 in THP-1 cells. Reduced SCN4A expression induced HCC-related genes, while increased SCN4A expression reduced their expression in HepG2 cells.Conclusion: The MP-related prognostic model comprising six MPRGs can effectively predict HCC prognosis, infer invasiveness, and guide drug therapy. SCN4A is identified as a suppressor gene in HCC.Keywords: hepatocellular carcinoma, macrophage polarization-related genes, tumor microenvironment, prognosis, SCN4A