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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2019

Open Access 01-12-2019 | Metastasis | Research

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

Authors: Zhan-Hong Chen, Jing-Jing Qi, Qi-Nian Wu, Jia-Huan Lu, Ze-Xian Liu, Yun Wang, Pei-Shan Hu, Ting Li, Jin-Fei Lin, Xiang-Yuan Wu, Lei Miao, Zhao-Lei Zeng, Dan Xie, Huai-Qiang Ju, Rui-Hua Xu, Feng Wang

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2019

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Abstract

Background

Deregulation 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).

Methods

Analysis 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.

Results

EIF4A2 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.

Conclusions

EIF4A2 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.
Appendix
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Metadata
Title
Eukaryotic initiation factor 4A2 promotes experimental metastasis and oxaliplatin resistance in colorectal cancer
Authors
Zhan-Hong Chen
Jing-Jing Qi
Qi-Nian Wu
Jia-Huan Lu
Ze-Xian Liu
Yun Wang
Pei-Shan Hu
Ting Li
Jin-Fei Lin
Xiang-Yuan Wu
Lei Miao
Zhao-Lei Zeng
Dan Xie
Huai-Qiang Ju
Rui-Hua Xu
Feng Wang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2019
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-019-1178-z

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