Aurora-A Promotes Lenvatinib Resistance Experimentally Through Hsa-circ-0058046/miR-424-5p/FGFR1 Axis in Hepatocellular Carcinoma

Overview

Journal Int J Immunopathol Pharmacol

Publisher Sage Publications

Date 2025 Feb 3

PMID 39895095

Authors

Mubalake Abudoureyimu

Ni Sun

Weiwei Chen

Xinrong Lin

Fan Pan

Rui Wang

Affiliations

Soon will be listed here.

Abstract

Objective: This study aimed to investigate whether the dysregulation of Aurora-A is involved in lenvatinib resistance in hepatocellular carcinoma.

Methods: 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.

Results: 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.

Conclusion: 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.

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