EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling.
EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling.
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EYA2 通过 SOCS3 介导的 JAK/STAT 信号传导阻断来抑制肝细胞癌的进展
DOI：
10.1186/s12943-021-01377-9
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发表时间：
2021-05-27
期刊：
影响因子：
37.3
通讯作者：
Bian H
中科院分区：
文献类型：
--
作者：
Liu ZK;Li C;Zhang RY;Wei D;Shang YK;Yong YL;Kong LM;Zheng NS;Liu K;Lu M;Liu M;Hu CX;Yang XZ;Chen ZN;Bian H
背景体细胞突变参与了肝细胞癌（HCC）的发生发展，但其发生的遗传机制仍不清楚。我们报道EYA 2抑制HCC进展，而EYA 2（A510 E）突变减弱EYA 2的抑瘤作用。方法对6对人HCC原发肿瘤和匹配的癌旁组织进行全外显子组测序。以EYA 2为研究对象，采用实时荧光定量PCR、免疫印迹和免疫组化方法检测EYA 2在人肝癌组织中的表达水平。通过功能缺失和获得性研究、小鼠肝细胞特异性EYA 2缺失（Eya 2 −/−）和RNA测序分析，探讨EYA 2对肝癌细胞生长和转移的功能影响及其机制。EYA 2甲基化状态进行了评估，使用Sequenom MassARRAY和公开可用的数据analysis.ResultsA新的体细胞突变p.Ala510Glu的EYA 2被确定在肝癌组织。EYA 2在HCC中的表达下调，且与肿瘤大小（P= 0.001）、巴塞罗那临床肝癌分期（P= 0.016）和肿瘤分化程度（P= 0.048）相关。EYA 2高表达与HCC患者预后良好相关（P= 0.003）。功能丧失和功能获得实验的结果表明，EYA 2的敲低增强，而EYA 2的过表达减弱，肝癌细胞在体外的增殖，克隆形成，侵袭和迁移。EYA 2基因转染对裸鼠原位肝肿瘤的生长有一定的抑制作用。然而，EYA 2（A510 E）突变导致蛋白质降解的未折叠蛋白质的反应，从而削弱了EYA 2的抑制功能。小鼠肝细胞特异性EYA 2缺失显著促进二乙基亚硝胺诱导的HCC发展。EYA 2在HCC中也通过异常的CpG甲基化而下调。机械，EYA 2与DACH 1相结合，转录调节SOCS 3的表达，从而抑制肝癌的进展，通过SOCS 3介导的阻断JAK/STAT信号通路。结论在我们的研究中，我们确定并验证EYA 2作为一个肿瘤抑制基因在肝癌，提供了一个新的见解肝癌的发病机制。
BackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P= 0.001), Barcelona Clinic Liver Cancer stage (P= 0.016) and tumor differentiation (P= 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P= 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.
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影响因子：
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作者：
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通讯作者：
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