Work

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

Year: 2015

Type: article

Abstract: // Lihua Wu 1, 2, * , Haiyang Yu 1, * , Yuhan Zhao 1 , Cen Zhang 1 , Jiabei Wang 1 , Xuetian Yue 1 , Qifeng Yang 1, 3 , Wenwei Hu 1 1 Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA 2 First Affiliated Hospital, Zhejiang University, Hangzhou, China 3 Department 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 ABSTRACT 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.3017