Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA.
School of Medicine, Kansas University Medical Center, Kansas City, KS, USA.
J Pathol. 2023 Jan;259(1):46-55. doi: 10.1002/path.6018. Epub 2022 Nov 9.
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, but it did not fully recapitulate genetic models. D-dopachrome tautomerase (gene symbol DDT), commonly referred to as MIF2, is a functional homolog of MIF1, and both MIF1 and MIF2 can bind the cell surface receptor CD74 on multiple cell types to initiate a signaling cascade. It has been proposed that this interaction mediates part of the protumorigenic effects of MIF1 and MIF2 and may explain the discordance in prior studies. We hypothesized that MIF2 functions redundantly with MIF1 in BCa development and progression. The Cancer Genome Atlas (TCGA) analysis indicated MIF and DDT expression were increased in BCa patients compared to control. 4-Iodopyridine (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, wild-type (WT) and Mif1 animals were exposed to 0.05% BBN in drinking water for 16 weeks to initiate tumorigenesis and 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 whether MIF1/MIF2 functioned through CD74 in BCa, WT or Cd74 animals were used in the same BBN model. Although these animals were partially protected against BBN-induced BCa, 4-IPP did not enhance this effect. In conclusion, our data suggest that MIF2 mechanistically functions in a similar protumorigenic manner to MIF1, and this is at least partially through CD74. Dual inhibition of MIF homologs is more efficacious at reducing tumor burden in this model of BCa. © 2022 The Pathological Society of Great Britain and Ireland.
巨噬细胞移动抑制因子 1（MIF1）是一种多功能细胞因子，参与炎症和癌症。在先前的研究中，在验证的 N-丁基-N-（4-羟丁基）亚硝胺（BBN）膀胱癌（BCa）模型中，Mif1 的基因敲除导致非肌肉浸润性疾病的分期停滞。MIF1 的小分子抑制减少了与癌症相关的结果，但它并没有完全重现基因模型。D-多巴色素互变异构酶（基因符号 DDT），通常称为 MIF2，是 MIF1 的功能同源物，MIF1 和 MIF2 都可以结合多种细胞类型的细胞表面受体 CD74 以启动信号级联反应。有人提出，这种相互作用介导了部分 MIF1 和 MIF2 的促肿瘤作用，并且可能解释了先前研究中的不一致性。我们假设 MIF2 在 BCa 的发生和进展中与 MIF1 功能冗余。癌症基因组图谱（TCGA）分析表明，与对照相比，BCa 患者的 MIF 和 DDT 表达增加。4-碘吡啶（4-IPP），一种联合的 MIF1/MIF2 抑制剂，在预防 BCa 细胞系的细胞增殖方面比 MIF1 仅抑制剂 ISO-1 更有效。为了在体内评估这些发现，野生型（WT）和 Mif1 动物接受 0.05% BBN 饮用水 16 周以引发肿瘤发生，然后在接下来的 4 周内评估有无 4-IPP 存在时的肿瘤形成和进展。4-IPP 降低了 WT 动物的膀胱重量和 Mif1 动物的膀胱重量/肿瘤分期。为了确定 MIF1/MIF2 是否通过 BCa 中的 CD74 发挥作用，在相同的 BBN 模型中使用了 WT 或 Cd74 动物。尽管这些动物对 BBN 诱导的 BCa 有部分保护作用，但 4-IPP 并没有增强这种作用。总之，我们的数据表明，MIF2 在机制上以类似于 MIF1 的促肿瘤方式发挥作用，至少部分是通过 CD74。在这种 BCa 模型中，双重抑制 MIF 同源物更有效地减少肿瘤负担。2022 年英国和爱尔兰病理学学会。
