Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer

Journal of Experimental & Clinical Cancer Research

Jia-Huan Lu¹  Jin-Fei Lin¹  Ting Li¹  Huai-Qiang Ju¹  Rui-Hua Xu¹  Ze-Xian Liu¹  Feng Wang¹  Jing-Jing Qi¹  Pei-Shan Hu¹  Zhao-Lei Zeng¹  Yun Wang¹  Lei Miao¹  Zhan-Hong Chen²  Qi-Nian Wu³  Dan Xie³  Xiang-Yuan Wu⁴ 

[1] 0000 0001 2360 039X, grid.12981.33, Department of Medical Oncology of Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, 510060, Guangzhou, China;0000 0001 2360 039X, grid.12981.33, Department of Medical Oncology of Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfengdong Road, 510060, Guangzhou, China;0000 0004 1762 1794, grid.412558.f, Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China;0000 0001 2360 039X, grid.12981.33, Department of pathology of Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China;0000 0004 1762 1794, grid.412558.f, Department of Medical Oncology and Guangdong Key Laboratory of Liver Disease, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China;

关键词: Colorectal cancer;    Eukaryotic initiation factor 4A2 (EIF4A2);    PDX;    Silvestrol;    ZNF143;   

DOI  :  10.1186/s13046-019-1178-z

来源: publisher

【 摘 要 】

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 of EIF4A2.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.

【 授权许可】

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