HIF-2 alpha 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-2 alpha but not HIF-1 alpha. Consistently, ectopic expression of HIF-2 alpha but not HIF-1 alpha transcriptionally induced LIF expression levels in cells. Knockdown of endogenous HIF-2 alpha but not HIF-1 alpha by siRNA largely abolished the induction of LIF by hypoxia in cells. Furthermore, there is a strong association of HIF-2 alpha 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-2 alpha, which could be an important underlying mechanism for LIF overexpression in human cancers.