Pannequin Julie, Bonnans Caroline, Delaunay Nathalie, Ryan Joanne, Bourgaux Jean-François, Joubert Dominique, Hollande Frédéric
Centre National de la Recherche Scientifique UMR5203, Institut National de la Sante et de la Recherche Medicale U661, University of Montpellier I, Montpellier, France.
Cancer Res. 2009 Aug 1;69(15):6065-73. doi: 10.1158/0008-5472.CAN-08-2409. Epub 2009 Jul 21.
The Wnt and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Wnt 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 Wnt 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.
Wnt和Notch信号通路在结直肠癌（CRC）中均异常激活。我们最近发现，胃泌素原缺失可抑制Wnt信号传导并增加CRC细胞的杯状细胞分化。在此，我们表明，胃泌素原下调可恢复CRC细胞中早期分泌谱系标志物Math-1/Hath-1的表达，这是由于Notch信号传导受到抑制所致。这种效应是由β-连环蛋白/Tcf-4下游的Notch配体Jagged-1转录减少介导的。相应地，重组胃泌素原在胃泌素原缺失的细胞中依次激活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，表明存在从Notch到Wnt信号传导的反馈调节。这些结果表明，胃泌素原可能有助于维持CRC细胞中Wnt和Notch通路的同时激活，进一步凸显了针对胃泌素原进行CRC临床治疗的意义。
