Amplification of Tumor Hypoxic Responses by Macrophage Migration Inhibitory Factor–Dependent Hypoxia-Inducible Factor Stabilization

Abstract

Low oxygen tension-mediated transcription by hypoxiainducible factors (HIF) has been reported to facilitate tumor progression, therapeutic resistance, and metastatic adaptation. One previously described target of hypoxia-mediated transcription is the cytokine/growth factor macrophage migration inhibitory factor (MIF). In studies designed to better understand hypoxia-stimulated MIF function, we have discovered that not only is MIF induced by hypoxia in pancreatic adenocarcinoma but MIF is also necessary for maximal hypoxia-induced HIF-1A expression. Cells lacking MIF are defective in hypoxia-and prolyl hydroxylase inhibitor-induced HIF-1A stabilization and subsequent transcription of glycolytic and angiogenic gene products. Moreover, COP9 signalosome subunit 5 (CSN5), a component of the COP9 signalosome previously reported to functionally interact with MIF, has recently been shown to interact with and stabilize HIF-1A. Our results indicate that MIF interacts with CSN5 in pancreatic cancer cells and that MIF-depleted cells display marked defects in hypoxia-induced CSN5/HIF-1A interactions. This functional interdependence between HIF-1A and MIF may represent an important and previously unrecognized protumorigenic axis. [Cancer Res 2007;67(1):186-93]

Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

“…Similar to SRC-3, MIF was also overexpressed in patients with cancer [14][15][16][17]. Despite being overexpressed in cancer patients, the molecular mechanism responsible for MIF overexpression is not well understood.…”

“…Interestingly, both circulating and intracellular levels of MIF were elevated in patients with cancers, and the levels of MIF were closely correlated with tumor aggressiveness and metastatic potential, suggesting that MIF contributed to disease severity and survival [14][15][16][17]. Intracellular MIF interacted with the signalosome component JAB1/CSN5 and was shown to regulate both the activity of tumor suppressor p53 and the angiogenesis induced by hypoxia [17,18]. Interestingly, JAB1/CSN5 was further shown to interact with PR and SRC-1 and potentiated the activity of a variety of transcription factors known to associate with SRC-1, such as AP-1 and NF-κB [19][20][21].…”

CD74 expression and its therapeutic potential in thyroid carcinoma

“…The expression of MIF and/or CD74 has been explored in several forms of cancer (Ren et al 2005, Xu et al 2008, Nagata et al 2009, Cheng et al 2011a). In addition, MIF has been identified as a hypoxia-induced gene, and its expression serves to activate a proangiogenic transcriptional program (Winner et al 2007).…”

Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

“…The data suggest that MIF plays a critical role in hypoxia-induced PH, and its inhibition may be beneficial in preventing the development and progression of the disease. MIF itself can amplify hypoxia induced HIF-1α stabilization, leading to a positive feedback and expression of further MIF and other HIF-1 related factors (10,11). Once released into the extracellular environment, MIF can increase proliferation of cells including fibroblasts (12), endothelial cells (13) and smooth muscle cells (14,15), which are the main components of the vascular wall.…”