Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer
Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer
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真核起始因子4A2促进结直肠癌实验性转移和奥沙利铂耐药
DOI：
10.1186/s13046-019-1178-z
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发表时间：
2019-05-14
影响因子：
11.3
通讯作者：
Wang, Feng
中科院分区：
文献类型：
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作者：
Chen, Zhan-Hong;Qi, Jing-Jing;Wang, Feng
背景蛋白质翻译调控的失调是癌症的一个标志。真核起始因子4A 2（EIF 4A 2）是mRNA与核糖体结合所必需的，在翻译起始中起重要作用。然而，很少有人知道它在大肠癌（CRC）的功能。方法分析CRC转录组数据从TCGA确定，EIF 4A 2与预后不良。对297例结直肠癌及癌旁正常组织进行EIF 4A 2免疫组化研究。通过体外和体内细胞生物学试验研究EIF 4A 2对实验性转移的生物学功能和对奥沙利铂治疗的敏感性。通过生物信息学预测、染色质免疫沉淀（ChIP）和双荧光素酶报告基因分析，揭示EIF 4A 2调控的转录因子。多变量分析表明EIF 4A 2是总体、无疾病和无进展生存期的独立预测因子。基因敲除或小分子抑制剂西维司群导致EIF 4A 2功能障碍，可显着抑制CRC侵袭和迁移、球体形成，并增强体外和体内对奥沙利铂治疗的敏感性。值得注意的是，EIF 4A 2敲低也抑制了体内肺转移。qRT-PCR和免疫印迹分析将c-Myc鉴定为EIF 4A 2的下游靶标和效应子。ChIP和双荧光素酶报告基因检测证实ZNF 143是EIF 4A 2的特异性转录因子。结论EIF 4A 2促进大肠癌的实验性转移和奥沙利铂耐药。在细胞来源的异种移植物（CDX）和患者来源的异种移植物（PDX）模型中，司维司群可抑制肿瘤生长，并与奥沙利铂具有协同效应，可诱导细胞凋亡。
BackgroundDeregulation of protein translation control is a hallmark of cancers. Eukaryotic initiation factor 4A2 (EIF4A2) is required for mRNA binding to ribosome and plays an important role in translation initiation. However, little is known about its functions in colorectal cancer (CRC).MethodsAnalysis of CRC transcriptome data from TCGA identified that EIF4A2 was associated with poor prognosis. Immunohistochemistry study of EIF4A2 was carried out in 297 paired colorectal tumor and adjacent normal tissue samples. In vitro and in vivo cell-biological assays were performed to study the biological functions of EIF4A2 on experimental metastasis and sensitivity to oxaliplatin treatment. Bioinformatic prediction, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were carried out to unveil the transcription factor of EIF4A2 regulation.ResultsEIF4A2 Expression is significantly higher in colorectal tumors. Multivariate analysis suggests EIF4A2 as an independent predictor of overall, disease-free and progression-free survival. Dysfunction of EIF4A2 by genetic knock-down or small-molecule inhibitor silvestrol dramatically inhibited CRC invasion and migration, sphere formation and enhanced sensitivity to oxaliplatin treatment in vitro and in vivo. Notably, EIF4A2 knock-down also suppressed lung metastasis in vivo. qRT-PCR and immunoblotting analyses identified c-Myc as a downstream target and effector of EIF4A2. ChIP and dual-luciferase reporter assays validated the bioinformatical prediction of ZNF143 as a specific transcription factor ofEIF4A2.ConclusionsEIF4A2 promotes experimental metastasis and oxaliplatin resistance in CRC. Silvestrol inhibits tumor growth and has synergistic effects with oxaliplatin to induce apoptosis in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models.