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.
Increase of calcium levels in epithelial cells induces translocation of calcium-binding proteins migration inhibitory factor-related protein 8 (MRP8) and MRP14 to keratin intermediate filaments
