Urbach Achia, Yermalovich Alena, Zhang Jin, Spina Catherine S, Zhu Hao, Perez-Atayde Antonio R, Shukrun Rachel, Charlton Jocelyn, Sebire Neil, Mifsud William, Dekel Benjamin, Pritchard-Jones Kathy, Daley George Q
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;
Genes Dev. 2014 May 1;28(9):971-82. doi: 10.1101/gad.237149.113. Epub 2014 Apr 14.
Wilms Tumor, the most common pediatric kidney cancer, evolves from the failure of terminal differentiation of the embryonic kidney. Here we show that overexpression of the heterochronic regulator Lin28 during kidney development in mice markedly expands nephrogenic progenitors by blocking their final wave of differentiation, ultimately resulting in a pathology highly reminiscent of Wilms tumor. Using lineage-specific promoters to target Lin28 to specific cell types, we observed Wilms tumor only when Lin28 is aberrantly expressed in multiple derivatives of the intermediate mesoderm, implicating the cell of origin as a multipotential renal progenitor. We show that withdrawal of Lin28 expression reverts tumorigenesis and markedly expands the numbers of glomerulus-like structures and that tumor formation is suppressed by enforced expression of Let-7 microRNA. Finally, we demonstrate overexpression of the LIN28B paralog in a significant percentage of human Wilms tumor. Our data thus implicate the Lin28/Let-7 pathway in kidney development and tumorigenesis.
肾母细胞瘤是最常见的儿童肾癌，它由胚胎肾终末分化失败演变而来。我们在此表明，小鼠肾脏发育过程中异时调节因子Lin28的过表达通过阻断肾祖细胞的最后一波分化，显著扩增了肾祖细胞，最终导致一种与肾母细胞瘤极为相似的病理状况。利用谱系特异性启动子将Lin28靶向特定细胞类型，我们发现只有当Lin28在中间中胚层的多个衍生物中异常表达时才会出现肾母细胞瘤，这表明起源细胞是一种多能肾祖细胞。我们表明，Lin28表达的去除可逆转肿瘤发生，并显著增加肾小球样结构的数量，且Let-7 microRNA的强制表达可抑制肿瘤形成。最后，我们证实在相当比例的人类肾母细胞瘤中LIN28B旁系同源物过表达。因此，我们的数据表明Lin28/Let-7通路参与肾脏发育和肿瘤发生。
