Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma

Objective: Resveratrol(Res) is a promising anticancer drug against hepatocellular carcinoma(HCC), but whether its anti-HCC effects implicate mitophagy remains unclear. Therefore, we aimed to explore the specific role of Res in mitophagy and the related mechanisms during the treatment of HCC.Methods: Hep G2 cells and tumor-grafted nude mice were used to investigate the effects of low-, middleand high-dose of Res on HCC progression and mitophagy in vitro and in vivo, respectively. A series of approaches including cell counting kit-8, flow cytometry, wound healing and transwell assays were used to evaluate tumor cell functions. Transmission electron microscopy, immunofluorescence and Western blotting were used to assess mitophagy. Mitochondrial oxygen consumption rate, reactive oxygen species and membrane potential were used to reflect mitochondrial function. After disrupting the expression of metastasis-associated lung adenocarcinoma transcript 1(MALAT1), mi R-143-3p, and ribonucleoside reductase M2(RRM2), the effects of the MALAT1/mi R-143-3p/RRM2 axis on cell function and mitophagy under Res treatment were explored in vitro. Additionally, dual-luciferase reporter and chromatin immunoprecipitation were used to confirm interactions between target genes.Results: Res significantly inhibited the proliferation and promoted apoptosis of HCC cells in vitro, while significantly suppressing tumor growth in a dose-dependent manner and inducing mitophagy and mitochondrial dysfunction in vivo. Interestingly, MALAT1 was highly expressed in HCC cells and its knockdown upregulated mi R-143-3p expression in HCC cells, which subsequently inhibited RRM2expression. Furthermore, in nude mice grafted with HCC tumors and treated with Res, the expression of MALAT1, mi R-143-3p and RRM2 were altered significantly. In vitro data further supported the targeted binding relationships between MALAT1 and mi R-143-3p and between mi R-143-3p and RRM2. Therefore,a series of cell-based experiments were carried out to study the mechanism of the MALAT1/mi R-143-3p/RRM2 axis involved in mitophagy and HCC; these experiments revealed that MALAT1 knockdown, mi R-143-3p mimic and RRM silencing potentiated the antitumor effects of Res and its activation of mitophagy.Conclusion: Res facilitated mitophagy in HCC and exerted anti-cancer effects by targeting the MALAT1/mi R-143-3p/RRM2 axis.