Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Nanshan District, Shenzhen 518060, China.
Department of pathology, the University of Hong Kong, Hong Kong SAR 999077, China.
Food Funct. 2021 Apr 26;12(8):3381-3392. doi: 10.1039/d1fo00664a.
The effect of non-cytotoxic doses of epigallocatechin-3-gallate (EGCG) on the metastatic capability of human hepatocellular carcinoma (HCC) cells was investigated in vitro and in vivo. miR483-3p, a microRNA whose expression correlates inversely with survival and positively with disease progression in HCC patients, was found to promote HCC cell migration and invasion in vitro as well as lung metastasis in nude mice established by the tail-vein injection of HCC cells. The induction of reactive oxygen species (ROS) and downregulation of antioxidant defense factors Nrf2 and SOD2 appeared to be an important underlying mechanism and treatment with a non-cytotoxic dose of EGCG effectively reversed the miR483-3p-induced enhancement of HCC cell migration and invasion in vitro. Moreover, administration through drinking water at doses (0.1% and 0.5% EGCG solution, respectively) equivalent to the intake of regular to heavy tea drinkers could also significantly inhibit lung metastasis of HCC cells based on the estimation from the USDA Database for the Flavonoid Content of Selected Foods and FDA guidelines for the conversion of animal dose to human equivalent dose. EGCG also significantly counteracted the miR483-3p-induced alteration in the expression of epithelial-mesenchymal transition (EMT) markers, E-cadherin and vimentin, and downregulated the endogenous expression of miR483-3p in HCC cells through an epigenetic mechanism that led to the hypermethylation of the miR483-3p promoter region. The data from our study illustrate that miR483-3p promotes HCC metastasis likely through the induction of oxidative stress and uncover a novel role of EGCG for protection against miR483-3p-mediated HCC metastasis via the epigenetic modulation of miR483-3p expression. These findings therefore provide further evidence supporting that regular tea consumption may contribute to protection against miR-483-3p-induced ROS and the associated HCC progression.
体外和体内研究了非细胞毒性剂量表没食子儿茶素没食子酸酯 (EGCG) 对人肝癌 (HCC) 细胞转移能力的影响。发现 miR483-3p 是一种 miRNA，其表达与 HCC 患者的存活率呈负相关，与疾病进展呈正相关，可促进 HCC 细胞在体外迁移和侵袭，并促进 HCC 细胞通过尾静脉注射在裸鼠体内形成肺转移。诱导活性氧 (ROS) 和下调抗氧化防御因子 Nrf2 和 SOD2 似乎是一个重要的潜在机制，用非细胞毒性剂量的 EGCG 处理可有效逆转 miR483-3p 诱导的 HCC 细胞迁移和侵袭增强。此外，通过饮用水给药（分别为 0.1%和 0.5%EGCG 溶液），剂量相当于常规至重度饮茶者的摄入量，也可以根据 USDA 数据库中选定食物的类黄酮含量和 FDA 指南中动物剂量到人类等效剂量的转换来显著抑制 HCC 细胞的肺转移。EGCG 还显著逆转了 miR483-3p 诱导的上皮-间充质转化 (EMT) 标志物 E-钙粘蛋白和波形蛋白表达的改变，并通过导致 miR483-3p 启动子区域超甲基化的表观遗传机制下调 HCC 细胞中内源性 miR483-3p 的表达。我们的研究数据表明，miR483-3p 可能通过诱导氧化应激促进 HCC 转移，并揭示了 EGCG 通过表观遗传调控 miR483-3p 表达来预防 miR483-3p 介导的 HCC 转移的新作用。这些发现因此提供了进一步的证据，支持了有规律的饮茶可能有助于预防 miR-483-3p 诱导的 ROS 和相关的 HCC 进展。
