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

Background and Purpose 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. Experimental Approach Multilocular HCC was induced using the diethylnitrosamine/carbon tetrachloride (DEN/CCl 4 ) 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. Key Results DEN/CCl 4 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. Conclusion and Implications 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.