The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells
The Wnt Target Jagged-1 Mediates the Activation of Notch Signaling by Progastrin in Human Colorectal Cancer Cells
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DOI：
10.1158/0008-5472.can-08-2409
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发表时间：
2009-08-01
期刊：
影响因子：
11.2
通讯作者：
Hollande, Frederic
中科院分区：
文献类型：
--
作者：
Pannequin, Julie;Bonnans, Caroline;Hollande, Frederic
Whit和Notch信号通路在结直肠癌（CRC）中均异常激活。我们最近发现前胃泌素消耗抑制Writ信号传导并增加CRC细胞的杯状细胞分化。在这里，我们表明，前胃泌素下调恢复表达的CRC细胞的早期分泌谱系标志物数学-1/Hath-1由于抑制Notch信号。这种效应是由β-连环蛋白/Tcf-4下游的Notch配体jagged-1的转录减少介导的。因此，重组前胃泌素在前胃泌素耗尽的细胞中顺序地激活Wnt和Notch靶基因的转录。此外，这些细胞中jagged-1水平的恢复足以激活Tcf-4活性，表明发生了从Notch到Writ信号传导的反馈调节。这些结果表明，前胃泌素可能有助于维持CRC细胞中Wnt和Notch途径的伴随激活，进一步突出了前胃泌素靶向CRC临床管理的兴趣。[癌症研究2009;69（15）：6065-73]
The Whit and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Writ signaling and increased goblet cell differentiation of CRC cells. Here, we show that progastrin down-regulation restores the expression by CRC cells of the early secretory lineage marker Math-1/Hath-1 due to an inhibition of Notch signaling. This effect is mediated by a decreased transcription of the Notch ligand jagged-1, downstream of beta-catenin/Tcf-4. Accordingly, recombinant progastrin sequentially activated the transcription of Wnt and Notch target genes in progastrin-depleted cells. In addition, restoration of jagged-1 levels in these cells is sufficient to activate Tcf-4 activity, demonstrating the occurrence of a feedback regulation from Notch toward Writ signaling. These results suggest that progastrin could be instrumental in maintaining the concomitant activation of Wnt and Notch pathways in CRC cells, further highlighting the interest of progastrin targeting for the clinical management of CRC. [Cancer Res 2009;69(15): 6065-73]