Research Papers:

HIF-2α mediates hypoxia-induced LIF expression in human colorectal cancer cells

Lihua Wu _, Haiyang Yu, Yuhan Zhao, Cen Zhang, Jiabei Wang, Xuetian Yue, Qifeng Yang and Wenwei Hu

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Oncotarget. 2015; 6:4406-4417. https://doi.org/10.18632/oncotarget.3017

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Lihua Wu1,2,*, Haiyang Yu1,*, Yuhan Zhao1, Cen Zhang1, Jiabei Wang1, Xuetian Yue1, Qifeng Yang1,3, Wenwei Hu1

1Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA

2First Affiliated Hospital, Zhejiang University, Hangzhou, China

3Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, China

*These authors have contributed equally to this work

Correspondence to:

Wenwei Hu, e-mail: [email protected]

Qifeng Yang, e-mail: [email protected]

Keywords: Leukemia inhibitory factor, hypoxia, HIF-2α, hypoxia-responsive element

Received: December 02, 2014     Accepted: December 31, 2014     Published: January 22, 2015


Leukemia inhibitory factor (LIF), a multi-functional cytokine, has a complex role in cancer. While LIF induces the differentiation of several myeloid leukemia cells and inhibits their growth, it also promotes tumor progression, metastasis and chemoresistance in many solid tumors. LIF is frequently overexpressed in a variety of human tumors and its overexpression is often associated with poor prognosis of patients. Currently, the mechanism for LIF overexpression in tumor cells is not well-understood. Here, we report that hypoxia, a hallmark of solid tumors, induced LIF mRNA expression in human colorectal cancer cells. Analysis of LIF promoter revealed several hypoxia-responsive elements (HREs) that can specifically interact with and be transactivated by HIF-2α but not HIF-1α. Consistently, ectopic expression of HIF-2α but not HIF-1α transcriptionally induced LIF expression levels in cells. Knockdown of endogenous HIF-2α but not HIF-1α by siRNA largely abolished the induction of LIF by hypoxia in cells. Furthermore, there is a strong association of HIF-2α overexpression with LIF overexpression in human colorectal cancer specimens. In summary, results from this study demonstrate that hypoxia induces LIF expression in human cancer cells mainly through HIF-2α, which could be an important underlying mechanism for LIF overexpression in human cancers.

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