Intestinal epithelial Notch-1 protects from colorectal mucinous adenocarcinoma.
Intestinal epithelial Notch-1 protects from colorectal mucinous adenocarcinoma.
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DOI：
10.18632/oncotarget.26086
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发表时间：
2018-09-11
期刊：
影响因子：
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通讯作者：
Dahan S
中科院分区：
文献类型：
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作者：
Dunkin D;Iuga AC;Mimouna S;Harris CL;Haure-Mirande JV;Bozec D;Yeretssian G;Dahan S
越来越多的证据表明Notch-1信号与肠道结构和体内平衡的维持有关。常见的Notch-1通路转录因子重组结合蛋白抑制因子（RBP-J）功能障碍与上皮屏障完整性丧失和增殖性隐窝细胞向杯状细胞的异常转化有关。此外，我们最近发现上皮Notch-1在连接肠道先天免疫和适应性免疫中是不可或缺的，并且是支持保护性上皮促炎反应所必需的。然而，Notch-1在肠道肿瘤发生中的上皮特异性功能尚不清楚。我们培育了肠上皮细胞中选择性缺失Notch-1的绒毛蛋白- cre /Notch-1fl/fl （VN-/-）小鼠。小肠上皮Notch-1保留了屏障功能和完整性，而上皮Notch-1缺失会导致小鼠杯状细胞增生、自发性锯齿状病变、多灶低级别和高级别发育不良和结肠粘液瘤。随着时间的推移，VN-/-小鼠显示出结直肠粘液腺癌的高发生率，这与有丝分裂、血管生成和致瘤前基因表达水平的增加有关。最后，我们发现Notch-1在人类结直肠粘液腺癌中的表达与结直肠腺癌相比显著降低。综上所述，我们的研究结果揭示了Notch-1在控制肠道肿瘤发生中的一种新的关键保护作用。
Increasing evidence links Notch-1 signaling with the maintenance of intestinal architecture and homeostasis. Dysfunction in the common Notch-1 pathway transcription factor recombinant binding protein suppressor of hairless (RBP-J) is associated with loss of epithelial barrier integrity and aberrant conversion of proliferative crypt cells into goblet cells. Furthermore, we have recently discovered that epithelial Notch-1 is indispensable in bridging innate and adaptive immunity in the gut and is required for supporting protective epithelial pro-inflammatory responses. Yet, the epithelial specific function of Notch-1 in intestinal tumorigenesis remains unknown. We generated Villin-Cre/Notch-1fl/fl (VN-/-) mice that are selectively deficient in Notch-1 in intestinal epithelial cells. Intestinal epithelial Notch-1 preserved barrier function and integrity, whereas lack of epithelial Notch-1 induced goblet cell hyperplasia, spontaneous serrated lesions, multifocal low- and high-grade dysplasia and colonic mucinous neoplasms in mice. Over time, VN-/- mice displayed high occurrence of colorectal mucinous adenocarcinomas, which correlated with increased levels of mitogenic, angiogenic and pro-tumorigenic gene expression. Finally, we found that the expression of Notch-1 is significantly reduced in human colorectal mucinous adenocarcinoma when compared to colorectal adenocarcinoma. Taken together, our findings reveal a novel and critical protective role for Notch-1 in controlling intestinal tumorigenesis.