FGD5-AS1/miR-5590-3p/PINK1 induces Lenvatinib resistance in hepatocellular carcinoma.

BACKGROUND: Lenvatinib is a common systemic treatment for advanced hepatocellular carcinoma (HCC), the resistance to which presents a great challenge. However, the mechanism of lenvatinib resistance in HCC remains unclear. Therefore, elucidating the underlying and key regulatory molecular mechanisms of lenvatinib resistance is urgently needed.

METHODS: Bioinformatic enrichment analysis was used to investigate the gene associated with lenvatinib resistance. RT-PCR, Western blot, immunohistochemistry, and luciferase assays were used to explore the mechanisms of lenvatinib resistance. The effects of the FGD5-AS1/miR-5590-3p/PINK1 axis on lenvatinib resistance were evaluated by colony formation assay, cell viability, apoptosis, mitochondrial homeostasis, and morphology analyses.

RESULTS: Higher expression of PINK1 was observed in lenvatinib-resistant cells and tissues. PINK1 could be activated by increased FGD5-AS1 expression, thereby maintaining the mitochondrial structure and function and promoting the antioxidative stress response. FGD5-AS1/miR-5590-3p showed competitive regulation of PINK1, which affected lenvatinib sensitivity through regulation of mitochondrial structure and antioxidative stress.

CONCLUSIONS: PINK1 was identified as a key gene leading to lenvatinib resistance by maintaining the mitochondrial structure and function. The FGD5-AS1/miR-5590-3p/PINK1 axis may be a promising strategy to overcome lenvatinib resistance in treatment-negative patients.