Abstract #2186: Macrophage migration inhibitory factor (MIF) plays a role in proliferation and survival of Ewing tumor cells through the activation of Jak/Stat, Src and Rac1

Cytokines and chemokines are important regulators of cell signaling networks, which control cell growth, proliferation, differentiation, and survival. In normal cells, expression of cytokines and their mediated cell signaling pathways are tightly and accurately regulated. In contrast, it has been shown that cytokine signaling pathways are deregulated in many tumors. Thus, identification and understanding of deregulated cytokines and their related pathways can provide the unique and promising opportunity for better-targeted therapies of cancer. In this study, we investigated cytokines expression in Ewing tumor cell lines using Human cytokine protein array and we found Macrophage migration inhibitory factor (MIF) is a predominant cytokine in Ewing tumor cells. MIF has been known to be a proinflammatory cytokine but recently it was shown that MIF plays roles in several tumors such as proliferation, survival and apoptosis. To study the effects and molecular mechanisms of MIF on Ewing tumor cell growth and survival we established MIF deficient Ewing tumor cell lines using shRNA method. In our study it was found that the decreased MIF expression is significantly correlated to morphological change, deregulation of differentiation, decrease of proliferation and increase of apoptosis in Ewing tumor cells. Then several signal pathways were investigated to elucidate the molecular mechanism of MIF functions in Ewing tumor cells. It has been found that MIF is involved in the activation of Jak/Stat and Src pathways that regulate activation of Akt and Erk, which play key roles in the cell survival and proliferation. Related to the morphological change in MIF-deficient cells it was found that Rac1 activation is highly regulated by MIF. In general it is known that Rac1 is an essential regulator of cellular morphology and movement related to proliferation, differentiation and migration. Therefore our data implies that MIF might functionally contribute to Ewing tumor cell growth and metastasis. In conclusion, coupled with earlier studies about MIF-dependent effects on tumor growth our data suggested that MIF might be a promising target of Ewing tumor cells therapy.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2186.