Chen Jing, Chen Lihong, Lu Ting, Xie Yuqiong, Li Chunchun, Jia Zhenyu, Cao Jiang
Clinical Research Center, The Second Affiliated Hospital, Zhejiang University School of Medicine Hangzhou 310009, Zhejiang Province, China.
Institute of Occupational Diseases, Zhejiang Academy of Medical Sciences Hangzhou 310013, Zhejiang Province, China.
Int J Clin Exp Pathol. 2019 Sep 1;12(9):3222-3234. eCollection 2019.
Epigallocatechin-3-gallate (EGCG) is a natural product with potential anti-cancer property whose direct target has not been identified. This study intended to investigate ERα36, a new isoform of estrogen receptor alpha (ERa), as a therapeutic target of EGCG in hepatocellular carcinoma (HCC). In this work, we examined the expression level of ERs in HCC cell lines and a normal human liver cell line, and evaluated inhibition effect of EGCG on these cells , and further on Hep3B . The results showed that ERα36 was the main ER in HCC cells and served as a biomarker of responsiveness to EGCG inhibition, and there was a positive correlation between ERα36 expression level and inhibitory effect of EGCG as indicated by IC. experiments also showed dose-dependent inhibition of EGCG on ERα36 high-expressing Hep3B. EGCG exerted inhibition on Hep3B cells by both anti-proliferation and pro-apoptosis. ERα36-EGFR-Her-2 feedback loop, PI3K/Akt and MAPK/ERK pathways were inhibited, while caspase 3 was activated by EGCG in Hep3B cells, with p-ERK accumulated in cytoplasm. The inhibitory effect of EGCG was significantly attenuated when ERα36 was pre-activated. This is the first evidence that EGCG exerts its anti-cancer effect by inhibiting ERα36, followed with inhibition of the ERα36-EGFR-Her-2 feedback loop and PI3K/Akt, MAPK/ERK pathway, activation of caspase 3, and accumulation of p-ERK in cytoplasm. It suggests that ERα36 might be an efficient target of EGCG in HCC.
表没食子儿茶素-3-没食子酸酯（EGCG）是一种具有潜在抗癌特性的天然产物，其直接靶点尚未明确。本研究旨在探讨雌激素受体α（ERα）的一种新亚型ERα36作为EGCG在肝细胞癌（HCC）中的治疗靶点。在本研究中，我们检测了肝癌细胞系和正常人肝细胞系中ERs的表达水平，评估了EGCG对这些细胞以及对Hep3B细胞的抑制作用。结果表明，ERα36是肝癌细胞中的主要ER，是对EGCG抑制反应性的生物标志物，IC显示ERα36表达水平与EGCG抑制作用呈正相关。实验还表明EGCG对高表达ERα36的Hep3B细胞具有剂量依赖性抑制作用。EGCG通过抗增殖和促凋亡作用对Hep3B细胞发挥抑制作用。在Hep3B细胞中，EGCG抑制了ERα36-EGFR-Her-2反馈环、PI3K/Akt和MAPK/ERK信号通路，同时激活了caspase 3，p-ERK在细胞质中积累。当ERα36被预激活时，EGCG的抑制作用显著减弱。这是首次有证据表明EGCG通过抑制ERα36发挥抗癌作用，随后抑制ERα36-EGFR-Her-2反馈环和PI3K/Akt、MAPK/ERK信号通路，激活caspase 3，并使p-ERK在细胞质中积累。这表明ERα36可能是EGCG在肝癌中的有效靶点。
