Document Type

Journal Article

Authors

Yan Li, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Li Fu, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Jian-Biao Li, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Yanru Qin, Department of Clinical Oncology, First Affiliated Hospital, Zhengzhou University
Ting-Ting Zeng, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Jie Zhou, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Zhao-Lei Zeng, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Jinna Chen, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Ting-Ting Cao, Department of Clinical Oncology, University of Hong Kong
Xiaojiao Ban, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Chaonan Qian, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Zongwei Cai, Hong Kong Baptist UniversityFollow
Dan Xie, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Peng Huang, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Xin-Yuan Guan, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine

Department/Unit

Department of Chemistry

Title

Increased expression of EIF5A2, via hypoxia or gene amplification, contributes to metastasis and angiogenesis of esophageal squamous cell carcinoma

Language

English

Abstract

Background & Aims Solid tumors often become hypoxic, leading to activation of hypoxia-response genes. We investigated the effects of overexpression of the hypoxia response genes eIF5A2 in esophageal squamous cell carcinoma (ESCC). Methods We used quantitative real-time polymerase chain reaction and immunohistochemistry analyses to compare expression of eIF5A2 between paired ESCC samples and nontumor esophageal tissues, and fluorescence in situ hybridization to detect gene copy-number alterations. Luciferase reporter and chromatin immunoprecipitation assays were used to study interactions between eIF5A2 and hypoxia-inducible factor-1α (HIF1α). We determined the effects of eIF5A2 overexpression and knockdown in ESCC cell lines and growth of ESCC xenograft tumors in nude mice. Results Levels of eIF5A2 messenger RNA and protein were increased in >40% of ESCC samples compared with matched nontumor tissues, along with levels of HIF1α and vascular endothelial growth factor. Increased levels of EIF5A2 were significantly associated with ESCC metastasis to lymph nodes (P <.001) and tissue invasion (P =.037), and shorter survival times of patients (P <.001). Amplification of eIF5A2 was detected in 35.14% of ESCC samples that overexpressed eIF5A2. Hypoxia increased expression of eIF5A2 4- to 8-fold in ESCC cell lines; we observed bidirectional regulation between eIF5A2 and HIF1α. Transient transfection of ESCC cell lines with eIF5A2 increased their migratory and invasive abilities and markers of the epithelial to mesenchymal transition, and eIF5A2 knockdown or HIFα inhibition reduced these. In mice, xenograft tumors grown from ESCC cells that expressed eIF5A2 formed tumors more rapidly than cells that expressed only vector (controls); they also expressed higher levels of HIF1α and vascular endothelial growth factor, and formed more microvessels than controls. Knockdown of eIF5A2 in ESCC cells with interfering RNAs reduced their growth as xenograft tumors in mice, particularly when mice were given docetaxel or cisplatin. Conclusions eIF5A2 is overexpressed by gene amplification or hypoxia in ESCCs, and associated with up-regulation of HIF1α, metastasis, and shorter survival times of patients. Increased expression of eIF5A2 increases metastasis and angiogenesis in ESCC via the HIF1α-mediated signaling pathway. © 2014 by the AGA Institute.

Keywords

EMT, Gene Regulation, Oncogene, Oxygen

Publication Date

2014

Source Publication Title

Gastroenterology

Volume

146

Issue

7

Start Page

1701

End Page

1.70E+12

Publisher

WB Saunders

DOI

10.1053/j.gastro.2014.02.029

ISSN (print)

00165085

ISSN (electronic)

15280012

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