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.
Highlights
Leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine superfamily, is a pleiotropic protein expressed in multiple types of tissues and cells which regulates an array of important biological functions
The effective induction of hypoxia in cells was confirmed by the increased expression of VEGF, a hypoxia-responsive gene, at mRNA levels (Figure 1A) and the increased protein levels of HIF-1α and HIF-2α, two major hypoxia inducible factors (HIFs) (Figure 1B)
The specific pull-down of chromatin fragment containing hypoxia-responsive elements (HREs)-C and HRE-D but not HRE-A and HRE-B by the HIF-2α antibody under the hypoxic condition was confirmed by conventional PCR followed by agarose gel electrophoresis (Figure 2D). These results demonstrated that HIF-2α but not HIF-1α interacts with HRE-C and HRE-D in the LIF promoter under the hypoxic condition, which may mediate the hypoxia-induced LIF expression
Summary
Leukemia inhibitory factor (LIF), a member of the interleukin-6 cytokine superfamily, is a pleiotropic protein expressed in multiple types of tissues and cells which regulates an array of important biological functions. While early studies showed that LIF induces the differentiation of myeloid leukemia cells, recent studies from others and our laboratory demonstrated that LIF can inhibit cell differentiation and promote proliferation of many types of tumor cell lines [9,10,11]. LIF has been reported to promote the progression of malignancies of many solid tumors, including rhabdomyosarcoma, choriocarcinoma, melanoma, breast cancer and colorectal cancer [8, 10, 12,13,14,15,16,17]. While the mechanisms of the promoting effect of LIF on the development and progression of solid tumors are not wellunderstood, our recent study showed that LIF is a novel negative regulator of p53 through the Stat3/ID1/MDM2 www.impactjournals.com/oncotarget signaling in human colorectal cancers [17]. Overexpression of LIF promotes chemo-resistance in human colorectal cancers through attenuating p53 levels and functions in cells [17]
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