Mechanism of Lenvatinib Resistance via Exosomal miRNA-132/Nrf2 Axis in Hepatocellular Carcinoma.

[INTRODUCTION] Lenvatinib is a multiple receptor tyrosine kinase inhibitor and a first-line targeted therapy for hepatocellular carcinoma (HCC). However, its efficacy is insufficient because of acquired resistance. We investigated the role of exosomal miRNA exchange between resistant cancer cells and naive cancer cells in the development of lenvatinib resistance.

[MATERIALS AND METHODS] We generated lenvatinib-resistant (LVT-res) Huh7 and PLC cell lines. We first analyzed the miRNA expression profiles of Nrf2 in cancer using three public datasets and then investigated exosomal miRNA expressions. Exosomal miRNA-132 was found to be elevated in resistant cells compared with parental cells. The parental cells were cocultured with LVT-res cultured conditioned medium as recipient cells. We then compared the characteristics in parental cancer cells, resistant cells, and recipient cells.

[RESULTS] The proliferation and migration rates of recipient cells were significantly increased compared with the parental cells. Recipient cells also showed chemoresistance. The PTEN/GSK3β/Nrf2 signaling pathway was significantly upregulated in recipient cells compared with the parental cells. Inhibition of exosomal miRNA-132 reduced the malignant potential of recipient cells, chemoresistance, cell proliferation, and migration rates. Furthermore, the PTEN/GSK3β/Nrf2 signaling pathway was downregulated in recipient cells with inhibition of exosomal miRNA-132.

[CONCLUSION] Our study provides new findings on the role of the miRNA-132/Nrf2 axis in LVT-res cancer cells. This might be a potential therapeutic target in HCC chemoresistance.