1] Instituto de Investigaciones Biomédicas 'Alberto Sols', Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain [2] Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Swiss Institute for Experimental Cancer Research, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Oncogene. 2014 Apr 10;33(15):1975-85. doi: 10.1038/onc.2013.140. Epub 2013 Apr 29.
SPROUTY2 (SPRY2) is an intracellular regulator of receptor tyrosine kinase signaling involved in cell growth, differentiation and tumorigenesis. Here, we show that SPRY2 is a target gene of the Wnt/β-catenin pathway that is abnormally activated in more than 90% of colon carcinomas. In human colon cancer cells, SPRY2 expression is induced by β-catenin in co-operation with the transcription factor FOXO3a instead of lymphoid enhancer factor/T-cell factor proteins. We found binding of β-catenin to the SPRY2 promoter at FOXO3a response elements. In vivo, cells marked by nuclear β-catenin and FOXO3a express SPRY2 in proliferative epithelial tissues, such as intestinal mucosa and epidermis. Consistently, inducible β-catenin deletion in mice reduced Spry2 expression in the small intestine. Moreover, SPRY2 protein expression correlated with nuclear β-catenin and FOXO3a colocalization in human colon carcinomas. Importantly, the amount of SPRY2 protein correlated with shorter overall survival of colon cancer patients. Our data reveal SPRY2 as a novel Wnt/β-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer.
sprouty2 (sprY2) 是一种细胞内受体酪氨酸激酶信号转导的调节剂，参与细胞生长、分化和肿瘤发生。在这里，我们表明 sprY2 是 Wnt/β-catenin 通路的靶基因，在超过 90%的结肠癌中异常激活。在人结肠癌细胞中，sprY2 的表达由β-catenin 与转录因子 FOXO3a 共同诱导，而不是淋巴增强因子/T 细胞因子蛋白。我们发现β-catenin 在 FOXO3a 反应元件上与 sprY2 启动子结合。在体内，核β-catenin 和 FOXO3a 标记的细胞在增殖性上皮组织中表达 sprY2，如肠黏膜和表皮。一致地，在小鼠中诱导β-catenin 缺失可减少小肠中的 Spry2 表达。此外，sprY2 蛋白表达与人类结肠癌中核β-catenin 和 FOXO3a 的共定位相关。重要的是，sprY2 蛋白的含量与结肠癌患者的总生存时间较短相关。我们的数据揭示了 sprY2 作为一种新的 Wnt/β-catenin 和 FOXO3a 靶基因，提示结肠癌预后不良。
