Macrophage migration inhibitory factor exerts pro-proliferative and anti-apoptotic effects via CD74 in murine hepatocellular carcinoma.

<bold>Background and Purpose: </bold>Macrophage migration inhibitory factor (MIF) is an inflammatory and chemokine-like protein expressed in different inflammatory diseases as well as solid tumours. CD74-as the cognate MIF receptor-was identified as an important target of MIF. We here analysed the role of MIF and CD74 in the progression of hepatocellular carcinoma (HCC) in vitro and in vivo.<bold>Experimental Approach: </bold>Multilocular HCC was induced using the diethylnitrosamine/carbon tetrachloride (DEN/CCl4 ) model in hepatocyte-specific Mif knockout (Mif Δhep ), Cd74-deficient, and control mice. Tumour burden was compared between the genotypes. MIF, CD74 and Ki67 expression were investigated in tumour and surrounding tissue. In vitro, the effects of the MIF/CD74 axis on the proliferative and apoptotic behaviour of hepatoma cells and respective signalling pathways were assessed after treatment with MIF and anti-CD74 antibodies.<bold>Key Results: </bold>DEN/CCl4 treatment of Mif Δhep mice resulted in reduced tumour burden and diminished proliferation capacity within tumour tissue. In vitro, MIF stimulated proliferation of Hepa 1-6 and HepG2 cells, inhibited therapy-induced cell death and induced ERK activation. The investigated effects could be reversed using a neutralizing anti-CD74 antibody, and Cd74-/- mice developed fewer tumours associated with decreased proliferation rates.<bold>Conclusion and Implications: </bold>We identified a pro-tumorigenic role of MIF during proliferation and therapy-induced apoptosis of HCC cells. These effects were mediated via the MIF cognate receptor CD74. Thus, inhibition of the MIF/CD74 axis could represent a promising target with regard to new pharmacological therapies aimed at HCC. [ABSTRACT FROM AUTHOR]