Macrophage Migration Inhibitory Factor promotes HCC progression in vivo via the receptor CD74

Background and Aims:

Macrophage Migration Inhibitory Factor (MIF) is a proinflammatory cytokine with chemokine-like functions. Analysis of the GEPIA database revealed an increased expression of MIF in human hepatocellular (HCC) tumor tissue and high expression levels were associated with decreased survival in HCC patients. Referring to the MIF receptors, CD74 has been identified as an important target of MIF in malignant diseases. In this study, we analyze the functional role of MIF and its receptor CD74 in HCC progression in vitro and in vivo using an experimental murine model of HCC.

Methods:

HCC induction was induced in mice with a hepatocyte-specific Mif depletion (AlfpCre⁺Mif ^flox/flox mice, Mif ^Δhep), CD74 deficient mice and respective control mice using the in DEN/CCl4 model. Tumor size and number were analysed as well as immune cell infiltration via FACS analysis. Next, qPCR of differentiation and inflammatory marker were performed from whole liver and tumor tissue. In vitro, we performed proliferation and apoptosis/cell death assays.

Results:

Mif ^Δhep mice showed a reduced tumor burden in the DEN/CCl4 model compared to their control littermates. Furthermore, tumors in Mif ^Δhep displayed a diminuished proliferation rate and higher grades of differentiation. The intrahepatic and intratumoral immune cell repertoire was unaltered between the genotypes. In vitro, MIF stimulates the proliferation of the HCC cell line Hepa1 – 6 in a dose-dependent manner and inhibits sorafenib-induced cell death as evidenced by decreased Annexin V- and TUNEL-staining. Both effects can be reversed using a CD74 neutralizing antibody. In line with these results, CD74 deficient mice are less susceptible to hepatic carcinogenesis developing fewer and well-differentiated tumors.

Conclusion:

In this study, we identified a pro-tumorigenic role of MIF in hepatic carcinogenesis. MIF directly promotes proliferation of HCC cells, is protective during therapy-induced apoptosis and impacts differentiation of carcinogen-induced tumors in mice. Furthermore, in vitro and in vivo studies implicate that these effects are mediated via the receptor CD74. In conclusion, the inhibition of the MIF/CD74 axis could present a promising target for the improvement of HCC-directed therapies.