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Open Access Highly Accessed Research article

Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1α in hepatocellular carcinoma

Lin Zhang13, Gang Huang5, Xiaowu Li1, Yujun Zhang1, Yan Jiang1, Junjie Shen2, Jia Liu2, Qingliang Wang2, Jin Zhu1, Xiaobin Feng1, Jiahong Dong4* and Cheng Qian2*

Author Affiliations

1 Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China

2 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China

3 Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing, China

4 Institute of Hepatobiliary Surgery, General Hospital of PLA, Beijing, 100853, PR China

5 Department of Medical Genetics, College of Basic Medicine, Third Military Medical University, Chongqing, China

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BMC Cancer 2013, 13:108  doi:10.1186/1471-2407-13-108

Published: 9 March 2013

Abstract

Background

High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. In this study, we investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT).

Methods

The expression of EMT markers was analyzed by immunohistochemistry. Effect of hypoxia on induction of EMT and ability of cell migration and invasion were performed. Luciferase reporter system was used for evaluation of Snail regulation by hypoxia-inducible factor -1α (HIF-1α).

Results

We found that overexpression of HIF-1α was observed in HCC liver tissues and was related to poor prognosis of HCC patients. HIF-1α expression profile was correlated with the expression levels of SNAI1, E-cadherin, N-cadherin and Vimentin. Hypoxia was able to induce EMT and enhance ability of invasion and migration in HCC cells. The same phenomena were also observed in CoCl2-treated cells. The shRNA-mediated HIF-1α suppression abrogated CoCl2-induced EMT and reduced ability of migration and invasion in HCC cells. Luciferase assay showed that HIF-1α transcriptional regulated the expression of SNAI1 based on two hypoxia response elements (HREs) in SNAI1 promoter.

Conclusions

We demonstrated that hypoxia-stabilized HIF1α promoted EMT through increasing SNAI1 transcription in HCC cells. This data provided a potential therapeutic target for HCC treatment.

Keywords:
Epithelial-mesenchymal transition; Hypoxia; Hypoxia-inducible factor-1α; SNAI1; Hepatocellular carcinoma