Role of MIF1/MIF2/CD74 interactions in bladder cancer.

Macrophage migration inhibitory factor (MIF1) is a pleiotropic cytokine involved in inflammation and cancer. Genetic knockout of Mif1 in the validated N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) model of bladder cancer (BCa) resulted in stage arrest at non-muscle invasive disease in prior studies. Small molecule inhibition of MIF1 reduced cancer-associated outcomes however it did not fully recapitulate genetic models. D-dopachrome tautomerase (gene symbol DDT) - commonly referred to as MIF2 is a functional homologue of MIF1, and both MIF1 and MIF2 can bind the cell surface receptor CD74 on multiple cell types to initiate a signaling cascade. This interaction has been proposed to mediate part of the pro-tumorigenic effects of MIF1 and MIF2 and may explain the discordance in prior studies. We hypothesized MIF2 functions redundantly with MIF1 in BCa development and progression. TCGA analysis indicated MIF and DDT expression were increased in BCa patients compared to control. 4-IPP, a combined MIF1/MIF2 inhibitor, was more efficacious than ISO-1, a MIF1 only inhibitor, in preventing cellular proliferation in BCa cell lines. To evaluate these findings in vivo, WT and Mif1-/- animals were exposed to 0.05% BBN in drinking water for 16 weeks to initiate tumorigenesis, then evaluated over the subsequent 4 weeks for tumor formation and progression in the presence or absence of 4-IPP. 4-IPP reduced bladder weights in WT animals and bladder weights/tumor stage in Mif1-/- animals. To determine if MIF1/MIF2 function through CD74 in BCa, WT or Cd74-/- animals were used in the same BBN model. While these animals were partially protected against BBN induced BCa, 4-IPP did not enhance this effect. In conclusion, our data suggest MIF2 mechanistically functions in a similar pro-tumorigenic manner to MIF1, and this is at least partially through CD74. Dual inhibition of MIF homologues is more efficacious at reducing tumor burden in this model of BCa. This article is protected by copyright. All rights reserved.

The Journal of pathology. 2022 Oct 10 [Epub ahead of print]

Benjamin L Woolbright, Ganeshkumar Rajendran, Erika Abbott, Austin Martin, Sarah Amalraj, Katie Dennis, Xiaogang Li, Joshua Warrick, John A Taylor

Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA., School of Medicine, Kansas University Medical Center, Kansas City, KS, USA., Department of Pathology, Kansas University Medical Center, Kansas City, KS, USA., Department of Medicine, Mayo Clinic, Rochester, MN, USA., Department of Pathology and Laboratory Medicine, The Pennsylvania State University, Hershey, PA, USA.

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