Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Department of Obstetrics and Gynecology, Graduate School of Medicine, Nagoya University, Nagoya, Japan.
J Pathol. 2019 Jan;247(1):86-98. doi: 10.1002/path.5171. Epub 2018 Nov 29.
Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3 /Irx5 mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3 cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β-catenin-signalling. In contrast, IRX5 cells displayed activation of Hippo and non-canonical WNT-signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
维尔姆斯瘤是一种具有肾脏发育停滞特征的儿科恶性肿瘤。在这里，我们证明了同源异型盒基因 IRX3 和 IRX5 对于哺乳动物肾发生是必需的，并支配威尔姆斯瘤的分化。IRX3 / Irx5 基因敲除小鼠表现出明显减少的胚胎肾单位形成。在人类胎儿肾和威尔姆斯瘤中，IRX5 的表达在早期增殖性胚基中已经被激活，而 IRX3 蛋白水平在管状分化时达到峰值。因此，威尔姆斯瘤的原位异种移植小鼠模型表明，IRX3 细胞形成以未成熟间充质和活跃的经典 WNT/β-catenin 信号传导为特征的大体积肾肿瘤。相比之下，IRX5 细胞表现出 Hippo 和非经典 WNT 信号的激活，并产生富含小管形成的小肿瘤。我们的研究结果表明，促进 IRX3 信号传导或抑制 IRX5 信号传导可能是威尔姆斯瘤分化治疗的一种途径，其中 WNT5A 是强制管状成熟的候选分子。© 2018 作者。约翰威立父子公司代表英国和爱尔兰病理学学会出版的《病理学杂志》。
