HIF-2α mediates hypoxia-induced LIF expression in human colorectal cancer cells.
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.
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.|First Affiliated Hospital, Zhejiang University, Hangzhou, China.
Lihua
L
Wu
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.
Haiyang
H
Yu
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.
Yuhan
Y
Zhao
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.
Cen
C
Zhang
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.
Jiabei
J
Wang
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.
Xuetian
X
Yue
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.|Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, China.
Qifeng
Q
Yang
Rutgers Cancer Institute of New Jersey, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.
Wenwei
W
Hu
D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D053605:Leukemia Inhibitory Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C507837:LIF protein, human