Epigallocatechin Gallate Derivative Y6 Reverses Oxaliplatin Resistance in Hepatocellular Carcinoma via Targeting the MiR-338-3p/HIF-1α/TWIST Axis to Inhibit EMT.

Chuan Huang, Si-Hong Wang, Tao-Tao Liu, Mei-Yi Wu, Kai-Ning Cai, Zhan-Hong Xie, Rui-Qiang Zhao, Yan Wen
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Abstract

Background: The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y6 was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y6 on oxaliplatin resistance in HCC.

Methods: MTT was used to determine the reversal effect of Y6 on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y6 or EGCG in drugresistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/Twist proteins, and EMT-related proteins.

Results: We found that Y6 could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y6 plus OXA group. At the same time, Y6 could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and Twist was down-regulated.

Conclusion: Y6 significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y6 could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

表没食子儿茶素没食子酸酯衍生物 Y6 通过靶向 MiR-338-3p/HIF-1α/TWIST 轴抑制 EMT 逆转肝细胞癌的奥沙利铂耐药性
背景:奥沙利铂(OXA)耐药性的出现是晚期肝细胞癌(HCC)治疗的关键障碍之一。作为天然化合物表没食子儿茶素没食子酸酯(表没食子儿茶素-3-没食子酸酯,EGCG)的乙基衍生物,Y6被发现能够提高HCC细胞对多柔比星的敏感性。本研究旨在探讨 Y6 对 HCC 奥沙利铂耐药性的影响:方法:采用 MTT 测定 Y6 对奥沙利铂耐药性的逆转作用。为了进一步探讨逆转机制,我们对耐药细胞单独或与 Y6 或 EGCG 联合处理 OXA,并观察细胞的形态学变化。同时,我们还采用了Transwell试验来检测细胞的侵袭和迁移能力。此外,还进行了实时 PCR 和 Western 印迹分析,以确定 miR-338-3p 基因、HIF-1α/Twist 蛋白和 EMT 相关蛋白的表达水平:结果:我们发现Y6能抑制HCC细胞的增殖,并有效逆转奥沙利铂耐药人肝癌细胞(SMMC-7721/OXA)对OXA的耐药性,其逆转效果比其主药EGCG更显著。对照组和OXA组的大部分细胞呈现典型的间质样细胞形态,而联合给药组的大部分细胞呈现典型的上皮样细胞形态,细胞的侵袭和迁移能力显著下降,尤其是Y6加OXA组。同时,Y6 能上调 EMT 上皮标志蛋白 E-cadherin,下调间质标志蛋白 Vimentin。此外,在联合用药组中,miR-338-3p的表达上调,而HIF-1α和Twist的表达下调:结论:Y6能明显增强耐药细胞对OXA的敏感性,这一过程可能与调控miR-338-3p/HIF-1α/TWIST通路抑制EMT有关。因此,Y6 可被视为一种有效的耐药性逆转剂,可提高肝癌患者的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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