EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3.
EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3.
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EFTUD2通过激活STAT3维持肿瘤细胞的存活并促进肝细胞癌进展
DOI：
10.1038/s41419-020-03040-5
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发表时间：
2020-10-06
影响因子：
9
通讯作者：
Hong J
中科院分区：
文献类型：
--
作者：
Tu M;He L;You Y;Li J;Yao N;Qu C;Huang W;Xu L;Luo R;Hong J
延伸因子Tu GTP结合域2（EFTUD 2）是一种剪接体GTP酶，在多器官发育和先天免疫中起着关键作用。已有报道EFTUD 2是一种新的抗HCV感染的宿主因子。然而，EFTUD 2在实体瘤（包括肝细胞癌（HCC））中的作用尚未研究。在这项研究中，我们研究了EFTUD 2在HCC中的分子功能。来自癌症基因组图谱（TCGA）的数据表明，与非肿瘤肝组织相比，HCC组织中的EFTUD 2上调。对两个独立的HCC队列进行的免疫组织化学分析证实了HCC组织中EFTUD 2的上调，并进一步表明EFTUD 2的高水平表达预测HCC患者的总体和无复发生存期较短。功能研究表明，siRNA干扰EFTUD 2表达显著抑制细胞活力，阻断细胞周期进程，促进肿瘤细胞凋亡，抑制转移，而EFTUD 2表达的增强促进肝癌细胞的增殖和迁移在体外和体内。令人惊讶的是，我们还发现通过慢病毒感染稳定敲低EFTUD 2表达对于HCC细胞是致命的。这一发现表明EFTUD 2对于维持HCC细胞的存活是必不可少的。从机制上讲，RNA测序和基因集富集分析（GSEA）表明，上皮-间充质转化（EMT）和JAK/STAT 3途径的基因集在EFTUD 2过表达细胞中富集。进一步验证表明，EFTUD 2过表达细胞表现出EMT样表型，并增强了STAT 3激活，而STAT 3抑制剂S3 I-201部分阻断了EFTUD 2过表达的这些促恶性效应。总之，我们报告EFTUD 2作为一种新的癌基因，有助于维持HCC细胞的存活，并通过激活STAT 3促进HCC进展。EFTUD 2在HCC组织中的高水平表达表明HCC患者的总体生存期和无复发生存期较短。
Elongation factor Tu GTP binding domain containing 2 (EFTUD2), a spliceosomal GTPase, plays a pivotal role in multiple organ development and innate immune. It has been reported that EFTUD2 is a new host factor with activity against HCV infection. However, the role of EFTUD2 in solid tumors, including hepatocellular carcinoma (HCC), remains unexplored. In this study, we investigated the molecular function of EFTUD2 in HCC. Data from The Cancer Genome Atlas (TCGA) indicated an upregulation of EFTUD2 in HCC tissues compared to that in nontumor liver tissues. Immunohistochemical analysis performed on two independent HCC cohorts confirmed the upregulation of EFTUD2 in HCC tissues and further suggested that a high level of EFTUD2 expression predicted shorter overall and recurrence-free survival in HCC patients. Functional studies suggested that siRNA interference with EFTUD2 expression significantly suppressed cell viability, blocked cell cycle progression, facilitated tumor cell apoptosis, and inhibited metastasis, while the enhancement of EFTUD2 expression promoted the proliferation and migration of HCC cells both in vitro and in vivo. Surprisingly, we also found that the stable knockdown of EFTUD2 expression via lentivirus infection was lethal for HCC cells. This finding suggested that EFTUD2 was essential for maintaining the survival of HCC cells. Mechanistically, RNA sequencing and gene set enrichment analysis (GSEA) suggested that the gene sets of epithelial–mesenchymal transition (EMT) and the JAK/STAT3 pathway were enriched in EFTUD2-overexpressing cells. Further verification indicated that EFTUD2-overexpressing cells exhibited an EMT-like phenotype and had enhanced STAT3 activation, while the STAT3 inhibitor S3I-201 partially blocked these pro-malignant effects of EFTUD2 overexpression. In summary, we report EFTUD2 as a novel oncogene that helps to maintain the survival of HCC cells and promotes HCC progression through the activation of STAT3. The high level of expression of EFTUD2 in HCC tissues indicates shorter overall and recurrence-free survival in HCC patients.
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