Abstract 1117: Macrophage migration inhibitory factor (MIF) plays a critical role in clear cell renal carcinoma

Abstract

Abstract Clear cell renal carcinoma (CCRC) is the most common form of renal cancer, resulting in 50,000 new cases per year in the US, and greater than 10,000 deaths. CCRC is frequently characterized by alterations in the von Hippel-Lindau protein (VHL), an E3 ligase that mediates oxygen dependent degradation of the alpha subunit of the hypoxia inducible factor (HIF). Activation of HIF and many of its transcriptional target genes are critical for renal tumorigenesis. The macrophage migration inhibitor factor (MIF) is a pleiotropic cytokine that has roles in inflammation, cell signaling, and cell cycle regulation. MIF is regulated by HIF, and is expressed in a variety of tumor types wherein MIF expression correlates with poor outcome. Functionally, MIF can negatively regulate p53, and thus may be particularly relevant in cancers like clear cell carcinoma in which p53 is not commonly mutated. The purpose if this study is to determine the role of MIF in CCRC. In order to determine if MIF is expressed in CCRC patient samples, we stained tumor microarrays with over 95 primary CCRC tumors for MIF expression. In keeping with its reported regulation by the VHL/HIF pathway, MIF demonstrated high expression in greater than 90% of the tumors compared to normal kidney samples. Likewise, in CCRC tumor cell lines MIF expression was highly expressed compared to cell lines in which VHL expression has been reconstituted. To determine the significance of MIF expression in CCRC tumor cell lines, MIF was depleted using two independent shRNAs and we observed significant decreases cell proliferation and clonogenic survival in a variety of CCRC cell lines. These observations were replicated by silencing the expression of the MIF receptor CD74, suggesting the MIF signaling pathway is intact and functional CCRC. At the mechanistic level, MIF is known to inhibit the function of p53 through promotion of MDM2 mediated degradation. To assess whether the role of MIF in CCRC is to regulate p53, we determined the effects on p53 signaling when MIF expression was inhibited. We found that inhibition of MIF lead to an increase in p53 stability and subsequent expression of the canonical p53 target gene p21. Together these observations suggest that MIF expression may play a critical role as a target of the HIF/VHL pathway that leads to the development of clear cell carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1117. doi:10.1158/1538-7445.AM2011-1117