Journal of Hepatocellular Carcinoma (Feb 2022)
MicroRNA-128-3p Mediates Lenvatinib Resistance of Hepatocellular Carcinoma Cells by Downregulating c-Met
Abstract
Xin Xu,1,2 Wenjing Jiang,1 Peng Han,1 Jingyan Zhang,3 Liquan Tong,3 Xueying Sun1 1Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China; 2Department of General Surgery, Daqing Oil Field General Hospital, Daqing, 163000, People’s Republic of China; 3Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, 163316, People’s Republic of ChinaCorrespondence: Xueying Sun, Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China, Email [email protected] Liquan Tong, Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, 163316, People’s Republic of China, Email [email protected]: 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.Keywords: hepatocellular carcinoma, lenvatinib, drug resistance, c-Met, microRNA-128-3p
