Identification and Significance of the Novel MDR Relevant Hub Genes in Drug-Resistant Hepatocellular Carcinoma

Abstract

Current chemotherapeutic efficacy is limited by the fast acquisition of multidrug resistance (MDR) with high side effects. In this study, 66 MDR-relevant hub genes in hepatocellular carcinoma (HCC) were identified by the 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. The prognostic risk models were established via the LASSO-Cox regression analysis. Based on the comparison of gene mutation frequency, tumor mutation burden (TMB) and immune infiltration in the high and low-risk groups, the relationships between the MDR-relevant hub genes and immune regulation were explored. The competitive endogenous RNA (ceRNA) networks of MDR-relevant hub genes and relevant non-coding RNAs (ncRNAs) were predicted and concluded to explore the potential mechanisms. Five MDR-relevant hub genes in drug-resistant HCC were finally confirmed, including ATP-binding cassette subfamily B member 6 (ABCB6), filamin C (FLNC), mutated in colorectal cancer (MCC), neuron navigator 3 (NAV3) and tripartite motif containing 9 (TRIM9). TRIM9 was identified as the most significant gene enhancing MDR, and its inhibition caused the IC50 of doxorubicin (DOX) decreased, and the intracellular uptake, retention and absorption of DOX increased significantly in HepG2/ADR cells. The results above may provide new insights into the mechanism of MDR development. With further exploration in future, the MDR-relevant hub genes, especially TRIM9 may be therapeutically targeted to improve the prognosis of drug-resistant HCC patients.

Note:
Funding Declaration: This work was supported by the National Natural Science Foundation of China (No. 82200513), Key Program of Shaanxi Provincial Science and Technology Department (No. 2022ZDLSF05-15, 2021SF-303 and 2022JQ-219), Talent Program of Xi’an Medical University (No. 2021TD02), Guangxi Innovation Driven Development Major Project (No. Guike AA20302013) and Nanning City Yongjiang Plan (No. 2020024).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Keywords: Hepatoma bioinformatics, multidrug resistance, hub genes, prognostic model, TRIM9