BEX1 mediates sorafenib resistance in hepatocellular carcinoma by regulating AKT signaling

Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). However, acquired tolerance after sorafenib treatment significantly limits its therapeutic efficacy, and the mechanisms underlying resistance remains poorly characterized. In this study, we identified BEX1 as key mediator of sorafenib resistance in HCC. We found that BEX1 expression was significantly reduced in sorafenib-resistant HCC cells and xenograft models, moreover, BEX1 expression in HCC tissues was down-regulated compared with that normal liver tissues in The Cancer Genome Atlas (TCGA) database, K-M analysis demonstrated that reduced BEX1 expression was correlated with poor clinical prognosis in HCC patients. Loss- and gain-of-function studies showed that BEX1 regulates the cell-killing ability of sorafenib. Further studies revealed that BEX1 renders HCC cells sensitive to sorafenib via induction of apoptosis and negatively regulates the phosphorylation of Akt. In summary, our study uncover BEX1 may serve as a promising predictive biomarker for the prognosis of patients with HCC.