MicroRNA-128-3p Mediates Lenvatinib Resistance of Hepatocellular Carcinoma Cells by Downregulating c-Met

OBJECTIVE: Lenvatinib is a first-line multikinase inhibitor for advanced hepatocellular carcinoma (HCC), but resistance to the drug remains a major hurdle for its long-term anti-cancer activity. This resistance is thought to be due to overexpression of c-Met. This study aims to identify potential upstream microRNAs (miRNAs) that regulate c-Met, investigate the underlying mechanisms, and seek potential strategies that may reverse such resistance. METHODS: Lenvatinib-resistant HCC (LR-HCC) cells were established from human HCC Huh7 and SMMC-7721 cells. Assays of cell proliferation, cell cycle distribution, apoptosis, RT-qPCR, Western blot analysis and immunohistochemistry were employed. Potential miRNAs were screened by miRNA-target prediction tools and their regulatory effects were evaluated by luciferase reporter assays. Xenograft tumor models were used to evaluate the therapeutic effects. RESULTS: LR-HCC cells were refractory to lenvatinib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure of cells to lenvatinib resulted in increased expression and phosphorylation of c-Met, and c-Met inhibition enhanced the effects of lenvatinib in suppressing LR-HCC cells. Among eleven miRNA candidates, miR-128-3p displayed the most vigorous activity to negatively regulate c-Met and was downregulated in LR-HCC cells. MiR-128-3p mimics inhibited proliferation and induced apoptosis of LR-HCC cells, and enhanced the effects of lenvatinib in cell culture and animal models. MiR-128-3p and c-Met participate in the mechanisms underlying lenvatinib resistance through regulating Akt that mediates the apoptotic pathway and ERK (extracellular-signal-regulated kinase) modulating cell cycle progression. CONCLUSION: The present results indicate that the miR-128-3p/c-Met axis may be potential therapeutic targets for circumventing lenvatinib resistance in HCC and warrant further investigation.