Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial–mesenchymaltransition
- Wei Zhu1,2,
- Mu-Yan Cai1,3,
- Zhu-Ting Tong1,2,
- Sui-Sui Dong4,
- Shi-Juan Mai1,2,
- Yi-Ji Liao1,2,
- Xiu-Wu Bian5,
- Marie C Lin1,6,
- Hsiang-Fu Kung1,6,
- Yi-Xin Zeng1,2,
- Xin-Yuan Guan1,4,
- Dan Xie1,2
- 1State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- 2Departments of Experimental Research, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- 3Department of Pathology, Cancer Center, Sun Yat-Sen University, Guangzhou, China
- 4Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
- 5Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
- 6State Key Laboratory of Oncology in South China, the Chinese University of Hong Kong, Hong Kong, China
- Correspondence to Dr Dan Xie, State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, No 651, Dongfeng Road East, 510060 Guangzhou, China;
- Revised 5 June 2011
- Accepted 21 June 2011
- Published Online First 3 August 2011
Background and Aims The authors have previously isolated a putative oncogene, eukaryotic initiation factor 5A2 (EIF5A2) from 3q26. In this study, EIF5A2 was characterised for its role in colorectal carcinoma (CRC) aggressiveness and underlying molecular mechanisms.
Methods The expression dynamics of EIF5A2 were examined by immunohistochemistry in a cohort of carcinomatous and non-neoplastic colorectal tissues and cells. A series of in-vivo and in-vitro assays was performed to elucidate the function of EIF5A2 in CRC and its underlying mechanisms.
Results The overexpression of EIF5A2 was examined by immunohistochemistry in 102/229 (44.5%) CRC patients, and it was significantly correlated with tumour metastasis and determined to be an independent predictor of shortened survival (p<0.05). Ectopic overexpression of EIF5A2 in CRC cells enhanced cell motility and invasion in vitro and tumour metastasis in vivo, and induced epithelial–mesenchymal transition (EMT). The depletion of EIF5A2 expression prevented CRC cell invasiveness and inhibited EMT. Importantly, the metastasis-associated protein 1 (MTA1) gene was identified as a potential downstream target of EIF5A2 in CRC cells, and knockdown of MTA1 eliminated the augmentation of carcinoma cell migration, invasion and EMT by ectopic EIF5A2. The overexpression of EIF5A2 in CRC cells substantially enhanced the enrichment of c-myc on the promoter of MTA1, and MTA1 upregulation by EIF5A2 was partly dependent on c-myc.
Conclusion The data suggest that EIF5A2 plays an important oncogenic role in CRC aggressiveness by the upregulation of MTA1 to induce EMT, and EIF5A2 could be employed as a novel prognostic marker and/or effective therapeutic target for CRC.
See Commentary, p 473
WZ, MYC and ZTT contributed equally to this work.
Funding This work is supported by grants from the Nature Science Foundation of China (no 30972884), the 973 Project of China (2010CB529400 and 2010CB912802) and the Program for Excellent Young Talents in Sun Yat-Sen University Cancer Center (no 303045134001).
Competing interests None.
Ethics approval This study was approved by the Institute Research Medical Ethics Committee of Sun Yat-Sen University, Guangzhou, China.
Provenance and Peer review Not commissioned; externally peer reviewed.