Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
Gut. 2012 Oct;61(10):1435-8. doi: 10.1136/gutjnl-2011-300842. Epub 2011 Dec 3.
Expression of the Wnt target gene ASCL2 is elevated in 78% of intestinal neoplasia datasets (Oncomine), suggesting a role for deregulated ASCL2 in the aetiology of intestinal tumourigenesis. Furthermore, ectopic expression of Ascl2 has previously been shown to lead to hyperplasia in the mouse. However, elevated levels of ASCL2 does not have an impact on the overall survival or recurrence-free survival rates in colorectal cancer patients. Here the authors use a novel mouse model to analyse the role of Ascl2 in intestinal tumourigenesis and address the controversy surrounding the relevance of this gene to the aetiology of colorectal cancer.
The authors have generated a mouse possessing a transgene carrying the Ascl2 gene together with its endogenous promoter and regulatory regions, thereby elevating Ascl2 expression in an authentic manner. The authors have further intercrossed these Ascl2 overexpressers to the classic Apc(Min) model, to study the consequence of elevated Ascl2 expression in intestinal tumourigenesis.
Here the authors genetically demonstrate that elevated expression of Ascl2 in a Wnt signalling dependent manner specifically in the stem cell compartment of the intestine neither increases tumour formation nor diminishes survival in a well established intestinal tumour model, the Apc(min) mouse.
The authors conclude that ectopic expression of Ascl2 is more important in the aetiology of neoplasia than overexpression of Ascl2.
在 78%的肠肿瘤数据集（Oncomine）中，Wnt 靶基因 ASCL2 的表达升高，这表明 ASCL2 失调在肠肿瘤发生的发病机制中起作用。此外，先前已经表明异位表达 Ascl2 会导致小鼠增生。然而，结直肠癌患者中 ASCL2 水平升高并不会影响总体生存率或无复发生存率。在这里，作者使用一种新型小鼠模型来分析 Ascl2 在肠肿瘤发生中的作用，并解决围绕该基因与结直肠癌发病机制相关性的争议。
作者生成了一种携带 Ascl2 基因及其内源性启动子和调节区的转基因小鼠，从而以真实的方式提高 Ascl2 的表达。作者进一步将这些 Ascl2 过表达小鼠与经典的 Apc(Min)模型杂交，以研究在肠肿瘤发生中升高的 Ascl2 表达的后果。
作者从遗传学上证明，Wnt 信号依赖性方式下，Ascl2 的表达升高，特别是在肠干细胞区室中，既不会增加肿瘤形成，也不会降低在一种成熟的肠肿瘤模型（Apc(Min)小鼠）中的生存率。
作者得出结论，异位表达 Ascl2 在肿瘤发生的发病机制中比过表达 Ascl2 更为重要。
