Polosukhina Dina, Love Harold D, Moses Harold L, Lee Ethan, Zent Roy, Clark Peter E
Oncol Res. 2017 Nov 2;25(9):1653-1664. doi: 10.3727/096504017X14992942781895. Epub 2017 Jul 10.
Wilms tumor (WT) is the most common renal malignancy in children and the fourth most common pediatric solid malignancy in the US. Although the mechanisms underlying the WT biology are complex, these tumors most often demonstrate activation of the canonical Wnt/β-catenin pathway. We and others have shown that constitutive activation of β-catenin restricted to the renal epithelium is sufficient to induce primitive renal epithelial tumors, which resemble human WT. Here we demonstrate that pharmacologic inhibition of β-catenin gene transcription with pyrvinium inhibits tumor growth and metastatic progression in a murine model of WT. Cellular invasion is significantly inhibited in both murine WT-like and human WT cells and is accompanied by downregulation of the oncogenes Myc and Birc5 (survivin). Our studies provide proof of the concept that the canonical Wnt/β-catenin pathway may be a novel therapeutic target in the management of WT.
肾母细胞瘤（WT）是儿童中最常见的肾脏恶性肿瘤，在美国是第四大常见的儿科实体恶性肿瘤。尽管WT生物学背后的机制很复杂，但这些肿瘤最常表现出经典Wnt/β-连环蛋白通路的激活。我们和其他人已经表明，仅限于肾上皮细胞的β-连环蛋白的组成性激活足以诱导出类似于人类WT的原始肾上皮肿瘤。在这里，我们证明用吡维铵对β-连环蛋白基因转录进行药理抑制可抑制WT小鼠模型中的肿瘤生长和转移进展。在小鼠WT样细胞和人类WT细胞中，细胞侵袭均受到显著抑制，并伴有癌基因Myc和Birc5（生存素）的下调。我们的研究提供了这样一个概念的证据，即经典Wnt/β-连环蛋白通路可能是WT治疗中的一个新的治疗靶点。
