Dvl2 promotes intestinal length and neoplasia in the ApcMin mouse model for colorectal cancer.
Dvl2 promotes intestinal length and neoplasia in the ApcMin mouse model for colorectal cancer.
复制标题
DOI：
10.1158/0008-5472.can-10-1616
复制
发表时间：
2010-08-15
期刊：
影响因子：
11.2
通讯作者：
Bienz M
中科院分区：
文献类型：
--
作者：
Metcalfe C;Ibrahim AE;Graeb M;de la Roche M;Schwarz-Romond T;Fiedler M;Winton DJ;Corfield A;Bienz M
APC 突变会导致 Wnt/β-连环蛋白信号传导激活，从而必然导致结直肠癌。同样，过表达的 Dvl 蛋白是 β-连环蛋白信号传导的有效激活剂。通过免疫组织化学筛选不同阶段结直肠肿瘤的大型组织微阵列，我们发现Dvl2在结直肠腺瘤和癌中具有强烈的过表达倾向，与核β-连环蛋白和Axin2（Wnt/β-连环蛋白信号传导的通用转录靶标）平行。此外，在结直肠癌的 ApcMin 模型中，Dvl2 的缺失以剂量依赖的方式减少了肠道肿瘤的数量。有趣的是，Dvl2 突变体的小肠缩短，部分反映了其隐窝直径和细胞大小的减小。与此一致的是，mTOR 信号传导在正常肠隐窝中高度活跃，其中 Wnt/β-连环蛋白信号传导活跃，并且激活的 mTOR 信号传导（通过磷酸化 4E-BP1 染色显示）可作为 ApcMin 突变腺瘤的诊断标志物。 RAD001（依维莫司）对 ApcMin 突变小鼠中 mTOR 信号传导的抑制可减少其肠道肿瘤负荷，与 Dvl2 缺失类似。 mTOR 信号传导在人类增生性息肉中也持续活跃，并且在腺瘤和癌中具有显着的活跃趋势。我们的结果表明 Dvl2 和 mTOR 与结直肠肿瘤的进展有关，并强调了它们作为结直肠癌治疗靶点的潜力。
APC mutations cause activation of Wnt/β-catenin signalling, which invariably leads to colorectal cancer. Similarly, overexpressed Dvl proteins are potent activators of β-catenin signalling. Screening a large tissue microarray of different staged colorectal tumours by immunohistochemistry, we found that Dvl2 has a strong tendency to be overexpressed in colorectal adenomas and carcinomas, in parallel to nuclear β-catenin and Axin2 (a universal transcriptional target of Wnt/β-catenin signalling). Furthermore, deletion of Dvl2 reduced the intestinal tumor numbers in a dose-dependent way in the ApcMin model for colorectal cancer. Interestingly, the small intestines of Dvl2 mutants are shortened, reflecting in part a reduction of their crypt diameter and cell size. Consistent with this, mTOR signalling is highly active in normal intestinal crypts where Wnt/β-catenin signalling is active, and activated mTOR signalling (as revealed by staining for phosphorylated 4E-BP1) serves as a diagnostic marker of ApcMin mutant adenomas. Inhibition of mTOR signalling in ApcMin mutant mice by RAD001 (everolimus) reduces their intestinal tumour load, similarly to Dvl2 deletion. mTOR signalling is also consistently active in human hyperplastic polyps, and has a significant tendency for being active in adenomas and carcinomas. Our results implicate Dvl2 and mTOR in the progression of colorectal neoplasia and highlight their potential as therapeutic targets in colorectal cancer.