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 diseases as well as solid tumours. Here, CD74 – as the cognate MIF receptor – was identified as an important target of MIF. We analysed the role of MIF and CD74 in the progression of hepatocellular carcinoma (HCC) in vitro and in vivo using an experimental murine HCC model. Experimental Approach: 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 impact of the MIF/CD74 axis on the proliferative and apoptotic behaviour of hepatoma cells was assessed after stimulation with MIF and anti-CD74 antibodies. Key Results: DEN/CCl4 treatment of Mif Δhep mice resulted in reduced tumour burden and diminished proliferation capacity within the tumour tissue. In vitro, MIF stimulated the proliferation of Hepa 1-6 cells and inhibited therapy-induced cell death as evidenced by TUNEL-staining. Both effects could be reversed using a neutralizing anti-CD74 antibody, and Cd74-/- mice developed fewer tumours associated with decreased proliferation rates. Conclusion and Implications: In this study, we identified a pro-tumorigenic role of MIF during proliferation and therapy-induced apoptosis of HCC cells. Furthermore, our study implicates that these effects are mediated via the MIF cognate receptor CD74. In conclusion, the inhibition of the MIF/CD74 axis could present a promising target with regard to prospective HCC-directed pharmacological therapies.