Current chemotherapeutic efficacy is limited by the rapid development of multidrug resistance (MDR) in hepatocellular carcinoma (HCC). In this study, 66 MDR-related hub genes in drug-resistant HCC were identified through combined analysis of differential expressed genes (DEGs), gene functional enrichment, Cox proportional regression, weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network construction. A prognostic risk model was established through the LASSO-Cox regression analysis. Based on the comparison of gene mutation frequency, tumor mutation burden (TMB) and immune infiltration in high- and low-risk groups, we explored the relationships between the MDR-related hub genes and immune regulation. The competitive endogenous RNA (ceRNA) network and associated non-coding RNAs (ncRNAs) were predicted to investigate the potential mechanisms. Five MDR-related hub genes in drug-resistant HCC were finally confirmed, namely ABCB6, FLNC, MCC, NAV3 and TRIM9. TRIM9 was identified as the most significant gene enhancing MDR. Inhibiting TRIM9 caused a decrease in the IC50 of doxorubicin (DOX), and significant increases in the intracellular uptake, retention and absorption of DOX in HepG2/ADR cells. These findings may provide new insights into the mechanism of MDR development. The MDR-related hub genes, especially TRIM9 may be targeted therapeutically to enhance the prognosis of patients with drug-resistant HCC.
Keywords: Hepatocellular carcinoma; Multidrug resistance; TRIM9.
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