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

Abstract

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.

Authors 15

1. Theresa Hildegard Wirtz Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

2. Alena Saal Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

3. Irina Bergmann Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

4. Petra Fischer Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

5. Daniel Heinrichs Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

6. Elisa Fabiana Brandt Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

7. Maria Teresa Koenen Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

8. Sonja Djudjai Aachen

   RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University

9. Kai Markus Schneider Aachen

   RWTH Aachen University · Universitätsklinikum Aachen

   Affiliation as printed

   RWTH Aachen University Hospital

10. Peter Boor Aachen

    RWTH Aachen University

    Affiliation as printed

    RWTH Aachen University

11. Richard Bucala

    Yale University

    Affiliation as printed

    Yale School of Medicine

12. Ralf Weiskirchen Aachen

    RWTH Aachen University

    Affiliation as printed

    RWTH Aachen University

13. Jürgen Bernhagen

    Ludwig-Maximilians-Universität München

    Affiliation as printed

    Ludwig-Maximilians-Universität München

14. Christian Trautwein Aachen Univ Hosp Aachen

    Universitätsklinikum Aachen

    Affiliation as printed

    Univ Hosp Aachen

15. Marie‐Luise Berres Aachen

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    RWTH Aachen University Hospital