MicroRNA-20a Suppresses Tumor Proliferation and Metastasis in Hepatocellular Carcinoma by Directly Targeting EZH1.
MicroRNA-20a Suppresses Tumor Proliferation and Metastasis in Hepatocellular Carcinoma by Directly Targeting EZH1.
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MicroRNA-20a 通过直接靶向 EZH1 抑制肝细胞癌中的肿瘤增殖和转移
DOI：
10.3389/fonc.2021.737986
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发表时间：
2021
影响因子：
4.7
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Zhang Q;Deng X;Tang X;You Y;Mei M;Liu D;Gui L;Cai Y;Xin X;He X;Huang J
目的肝细胞癌（Hepatocellular carcinoma，HCC）是最常见的原发性肝脏肿瘤，是世界范围内发病率和死亡率最高的疾病。大多数HCC患者被诊断为晚期肝癌，导致5年生存率非常低。因此，迫切需要开发靶向治疗。本研究旨在探讨miR-20 a/EZH1轴对肝癌细胞增殖和转移的影响及其机制，以及EZH1/EZH2抑制剂UNC1999对肝癌细胞的抑制作用。材料与方法采用实时荧光定量PCR（qRT-PCR）方法检测miR-20 a在人肝癌组织和细胞系中的表达。免疫组化和Western blotting分析蛋白表达。荧光素酶测定用于验证miR-20 a是否靶向EZH1或EZH2。在体内和体外研究了miR-20 a对肝癌进展的影响。在体内证实了UNC1999的肿瘤抑制作用。采用CCK-8法、创伤愈合法、细胞迁移和侵袭实验评价UNC1999与索拉非尼的协同作用。进行RNA测序（RNA-seq）以筛选在UNC 1999、索拉非尼和联合处理后Huh 7和SMMC 7721细胞系中差异表达的基因。结果miR-20 a在肝癌组织和肝癌细胞系中均呈低表达。MiR-20 a抑制SMMC 7721和Huh 7细胞的增殖和迁移。荧光素酶检测和Western blot分析的结果显示，miR-20 a直接靶向组蛋白甲基转移酶EZH1。我们证明miR-20 a负性调节EZH1的表达，并通过降低H3K27甲基化来抑制HCC的增殖和转移。我们发现UNC1999抑制肿瘤细胞的增殖，并增强索拉非尼的抑制作用。结论miR-20 a通过直接靶向EZH1抑制肝癌细胞的增殖和转移。UNC1999在体内可抑制肿瘤增殖，增加肝癌细胞系对索拉非尼的敏感性。
Purpose Hepatocellular carcinoma (HCC), a worldwide leading cause of morbidity and mortality, is the most frequent primary liver tumor. Most HCC patients are diagnosed with advanced liver cancer, resulting in a very low 5-year survival rate. Thus, there is an urgent need for the development of targeted therapies. In this study, we aimed to investigate the effect and mechanism of the miR-20a/EZH1 axis on the proliferation and metastasis of HCC and the inhibitory effect of the EZH1/EZH2 inhibitor UNC1999 on HCC. Materials and Methods The expression of miR-20a in human HCC tissues and cell lines was detected using quantitative real-time PCR (qRT-PCR). The expressions of proteins were analyzed with immunohistochemistry and Western blotting. Luciferase assay was used to verify whether miR-20a targets EZH1 or EZH2. The effect of miR-20a on HCC progression was studied in vivo and in vitro. The tumor inhibitory effect of UNC1999 was confirmed in vivo. CCK8 assay, wound healing assay, cell migration and invasion assay were used to evaluate the synergistic effect of UNC1999 with sorafenib. RNA sequencing (RNA-seq) was performed to screen the differentially expressed genes in the Huh7 and SMMC7721 cell lines after UNC1999, sorafenib, and combination treatments. Results In this study, miR-20a showed a lower expression in both HCC tissues and cell lines. MiR-20a inhibited the proliferation and migration of SMMC7721 and Huh7 cells. The results of the luciferase assay and Western blot analysis revealed that miR-20a directly targeted EZH1, a histone methyltransferase. We demonstrated that miR-20a negatively regulated the expression of EZH1 and inhibited the proliferation and metastasis of HCC by reducing H3K27 methylation. We found UNC1999 inhibited tumor cells proliferation and enhanced the inhibitory effect of sorafenib. Conclusion We demonstrated that miR-20a suppresses the tumor proliferation and metastasis in HCC by directly targeting EZH1. UNC1999 can inhibit tumor proliferation in vivo and increase the sensitivity of hepatoma cell lines to sorafenib.
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DOI：
10.1186/1756-9966-32-21
发表时间：
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期刊：
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