Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer
Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer
复制标题
DOI：
10.1073/pnas.0813221106
复制
发表时间：
2009-04-14
影响因子：
11.1
通讯作者：
Espinosa, Lluis
中科院分区：
文献类型：
--
作者：
Rodilla, Veronica;Villanueva, Alberto;Espinosa, Lluis
Notch与β-连环蛋白依赖性肿瘤发生有关;然而，导致Notch激活的机制以及Notch途径对结直肠癌的贡献尚未了解。通过微阵列分析，我们已经鉴定了Wnt/β-连环蛋白下游的一组基因（当阻断Wnt/β-连环蛋白时下调），其直接受Notch调节（在β-连环蛋白信号传导不存在的情况下，受γ-分泌酶抑制剂抑制并受活性Notch 1上调）。我们证明，Notch是下游的Wnt在结直肠癌细胞通过β-连环蛋白介导的转录激活的Notch配体锯齿状蛋白1。因此，活化的Notch 1的表达部分逆转了阻断Wnt/β-catenin通路在移植性肿瘤中的作用。C.在裸鼠中。将APC（Min/+）与Jagged（1+/Delta）小鼠杂交足以显著减小在APC突变体背景中产生的息肉的大小，表明Notch是由核β-连环蛋白诱导的肿瘤发生的重要调节剂。我们发现这种机制在家族性腺瘤性息肉病患者的人类肿瘤中起作用。我们的结论是Notch激活，完成β-连环蛋白介导的上调锯齿状蛋白1，是必需的肿瘤发生在肠道。Notch特异性基因签名足以阻断肿瘤中的分化并促进血管发生，而增殖取决于这两种途径。
Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s. c. in nude mice. Crossing APC(Min/+) with Jagged(1+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.