Xu Bin, Liang Xiangnan, Liu Wuguang, Wu BaiTong, Wang Qiuxiang, Kai Gong, Han Chun, Sun Binwen, Dong Bing, Dong Chengyong, Wang Liming
Engineering Research Center for New Materials and Precision Treatment Technology of Malignant Tumors Therapy, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Engineering Technology Research Center for Translational Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116027, China.
Hereditas. 2025 Jul 31;162(1):148. doi: 10.1186/s41065-025-00517-1.
BACKGROUND: Regorafenib serves as a second-line treatment for patients with advanced hepatocellular carcinoma (HCC). Microsomal epoxide hydrolase 1 (EPHX1) is closely associated with tumorigenesis and drug resistance. However, the relationship between EPHX1 and regorafenib resistance, as well as the underlying mechanisms in HCC, remains unclear. OBJECTIVE: To investigate the role and mechanisms of EPHX1 in mediating regorafenib resistance in HCC. METHODS: We assessed the protein expression levels of EPHX1 in human HCC tissues and adjacent non-tumor tissues. Subsequently, we constructed HCC cell lines with EPHX1 overexpression and knockdown using lentiviral vectors and stimulated these cells with varying concentrations of regorafenib. We then measured cell proliferation and apoptosis using flow cytometry and Western blotting. Additionally, we established xenograft tumor models to explore the impact of EPHX1 on the in vivo efficacy of regorafenib. Furthermore, we employed digital gene expression sequencing (DGE-seq) to investigate and validate the specific molecular mechanisms by which EPHX1 mediates regorafenib resistance in HCC cells. RESULTS: We found that EPHX1 protein levels were significantly higher in HCC tissues compared to adjacent non-tumor tissues. EPHX1 inhibited the effects of regorafenib on cell proliferation and apoptosis. Consistently, the efficacy of regorafenib was enhanced in vivo following EPHX1 knockdown. Moreover, KEGG pathway enrichment analysis of DGE-seq data indicated that the JAK/STAT signaling pathway is crucial for EPHX1-induced regorafenib resistance. Finally, EPHX1 suppressed regorafenib-induced inactivation of the JAK/STAT signaling pathway and blocking this pathway with HY-N1447 alleviated EPHX1-induced regorafenib resistance. CONCLUSION: In summary, we conclude that EPHX1 enhances regorafenib resistance in HCC by activating the JAK/STAT signaling pathway. Our findings suggest that EPHX1 is a key resistance-related gene, which has significant implications for the application of regorafenib in advanced HCC.
背景：瑞戈非尼是晚期肝细胞癌（HCC）患者的二线治疗药物。微粒体环氧化物水解酶1（EPHX1）与肿瘤发生和耐药性密切相关。然而，EPHX1与瑞戈非尼耐药性之间的关系以及在HCC中的潜在机制仍不清楚。 目的：探讨EPHX1在介导HCC对瑞戈非尼耐药中的作用及机制。 方法：我们评估了人HCC组织和邻近非肿瘤组织中EPHX1的蛋白表达水平。随后，我们使用慢病毒载体构建了EPHX1过表达和敲低的HCC细胞系，并用不同浓度的瑞戈非尼刺激这些细胞。然后，我们使用流式细胞术和蛋白质印迹法测量细胞增殖和凋亡。此外，我们建立了异种移植肿瘤模型，以探讨EPHX1对瑞戈非尼体内疗效的影响。此外，我们采用数字基因表达测序（DGE-seq）来研究和验证EPHX1介导HCC细胞对瑞戈非尼耐药的具体分子机制。 结果：我们发现HCC组织中EPHX1蛋白水平显著高于邻近非肿瘤组织。EPHX1抑制了瑞戈非尼对细胞增殖和凋亡的作用。同样，EPHX1敲低后，瑞戈非尼在体内的疗效增强。此外，DGE-seq数据的KEGG通路富集分析表明，JAK/STAT信号通路对EPHX1诱导的瑞戈非尼耐药至关重要。最后，EPHX1抑制了瑞戈非尼诱导的JAK/STAT信号通路失活，用HY-N1447阻断该通路可减轻EPHX1诱导的瑞戈非尼耐药。 结论：总之，我们得出结论，EPHX1通过激活JAK/STAT信号通路增强HCC对瑞戈非尼的耐药性。我们的研究结果表明，EPHX1是一个关键的耐药相关基因，这对瑞戈非尼在晚期HCC中的应用具有重要意义。
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