Abudoureyimu Mubalake, Sun Ni, Chen Weiwei, Lin Xinrong, Pan Fan, Wang Rui
Department of Medical Oncology, Affiliated Jinling Hospital, Medical School, Nanjing University, Nanjing, China.
Department of Medical Oncology, Affiliated Jinling Hospital, Nanjing Medical University, Nanjing, China.
Int J Immunopathol Pharmacol. 2025 Jan-Dec;39:3946320251316692. doi: 10.1177/03946320251316692.
This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance in hepatocellular carcinoma.
Bioinformatics tools and drug sensitivity assays were used to investigate the association between Aurora-A expression level and lenvatinib resistance in hepatocellular carcinoma cell lines. Cell function experiments had performed after treatment with lenvatinib and/or a selective Aurora-A inhibitor (MLN-8237). CircRNA microarray, RIP, RNA pull-down, and dual-luciferace reporter assay were performed to identify the downstream molecular mechanism of Aurora-A dysregulation.
Aurora-A expression was positively correlated with lenvatinib resistance in hepatocellular carcinoma cells. The Aurora-A selective inhibitor MLN-8237, in combination with lenvatinib, synergistically inhibited hepatocellular carcinoma cell proliferation in vitro and vivo, suggesting the Aurora-A might be a potential therapeutic target for lenvatinib resistance. Mechanistically, Aurora-A induced FGFR1 expression through the hsa-circ-0058046/miR-424-5p/FGFR1 axis. Aurora-A promotes lenvatinib resistance through hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma cells. The simultaneous inhibition of FGFR1 by the Aurora-A inhibitor MLN-8237 and lenvatinib overcame lenvatinib resistance in hepatocellular carcinoma cells.
Collectively, our findings indicate that Aurora-A promotes lenvatinib resistance through the hsa-circ-0058046/miR-424-5p/FGFR1 axis in hepatocellular carcinoma (HCC) cells. These results suggest that Aurora-A may serve as a therapeutic target for HCC patients exhibiting lenvatinib resistance. Furthermore, the combination of lenvatinib and MLN-8237 shows potential for clinical trials aimed at overcoming lenvatinib resistance.
本研究旨在探讨Aurora-A的失调是否与肝细胞癌对乐伐替尼的耐药性有关。
使用生物信息学工具和药物敏感性试验来研究Aurora-A表达水平与肝癌细胞系中乐伐替尼耐药性之间的关联。在用乐伐替尼和/或选择性Aurora-A抑制剂（MLN-8237）处理后进行细胞功能实验。进行环状RNA微阵列、RNA免疫沉淀、RNA下拉和双荧光素酶报告基因检测以确定Aurora-A失调的下游分子机制。
Aurora-A的表达与肝癌细胞中乐伐替尼的耐药性呈正相关。Aurora-A选择性抑制剂MLN-8237与乐伐替尼联合使用，在体外和体内协同抑制肝癌细胞增殖，提示Aurora-A可能是乐伐替尼耐药的潜在治疗靶点。机制上，Aurora-A通过hsa-circ-0058046/miR-424-5p/FGFR1轴诱导FGFR1表达。Aurora-A通过hsa-circ-0058046/miR-424-5p/FGFR1轴促进肝癌细胞对乐伐替尼的耐药性。Aurora-A抑制剂MLN-8237和乐伐替尼同时抑制FGFR1可克服肝癌细胞对乐伐替尼的耐药性。
总体而言，我们的研究结果表明，Aurora-A通过hsa-circ-0058046/miR-424-5p/FGFR1轴促进肝癌（HCC）细胞对乐伐替尼的耐药性。这些结果表明，Aurora-A可能是对乐伐替尼耐药的肝癌患者的治疗靶点。此外，乐伐替尼和MLN-8237的联合使用显示出在旨在克服乐伐替尼耐药性的临床试验中的潜力。
