Short chain fatty acids and colon cancer
Short chain fatty acids and colon cancer
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DOI：
10.1093/jn/132.12.3804s
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发表时间：
2002-12-01
影响因子：
4.2
通讯作者：
Velcich, A
中科院分区：
文献类型：
--
作者：
Augenlicht, LH;Mariadason, JM;Velcich, A
肠癌的发展涉及肠粘膜中复杂的遗传和表观遗传改变。APC-β-连环蛋白-TCF 4通路是启动肿瘤形成的主要信号通路，它调节细胞增殖和结肠细胞分化，但许多其他内在和外在信号也调节这些细胞成熟通路。挑战在于了解信号传导和细胞成熟如何也被营养剂调节。通过基因表达谱分析，我们已经深入了解了短链脂肪酸调节这些途径的机制，以及基因程序响应的差异，以及c-myc基因对肠细胞成熟的生理调节剂（如丁酸盐）与药理调节剂（如非甾体类药物舒林酸）的特异性调节。此外，我们使用了一个组合的基因表达谱的细胞培养舒林酸和舒林酸治疗1个月的受试者的人粘膜的反应，再加上小鼠遗传模型的方法，以确定细胞周期蛋白依赖性激酶抑制剂p21（WAF 1/Cip 1）作为一个重要的抑制APC启动的肠道肿瘤形成和肿瘤抑制舒林酸的必要组成部分。最后，由肠杯状细胞分泌的粘膜屏障是腔内容物和肠粘膜之间的界面。我们建立了一个小鼠遗传模型，其中Muc 2基因编码主要的肠粘蛋白的靶向失活。这些小鼠由于细胞不能合成和储存粘蛋白而没有可识别的杯状细胞。这导致肠隐窝结构的扰动，增加的细胞增殖和细胞迁移率，减少的细胞凋亡和发展的腺瘤和腺癌在小肠和大肠和直肠。
The development of intestinal cancer involves complex genetic and epigenetic alterations in the intestinal mucosa. The principal signaling pathway responsible for the initiation of tumor formation, the APC-beta-catenin-TCF4 pathway, regulates both cell proliferation and colonic cell differentiation, but many other intrinsic and extrinsic signals also modulate these cell maturation pathways. The challenge is to understand how signaling and cell maturation are also modulated by nutritional agents. Through gene expression profiling, we have gained insight into the mechanisms by which short chain fatty acids regulate these pathways and the differences in response of gene programs, and of the specific regulation of the c-myc gene, to physiological regulators of intestinal cell maturation, such as butyrate, compared with pharmacological regulators such as the nonsteroidal antiinflammatory drug sulindac. Moreover, we used a combination of gene expression profiling of the response of cells in culture to sulindac and the response of the human mucosa in subjects treated with sulindac for 1 month, coupled with a mouse genetic model approach, to identify the cyclin dependent kinase inhibitor p21(WAF1/Cip1) as an important suppressor of Apc-initiated intestinal tumor formation and a necessary component for tumor inhibition by sulindac. Finally, the mucous barrier, secreted by intestinal goblet cells, is the interface between the luminal contents and the intestinal mucosa. We generated a mouse genetic model with a targeted inactivation of the Muc2 gene that encodes the major intestinal mucin. These mice have no recognizable goblet cells due to the failure of cells to synthesize and store mucin. This leads to perturbations in intestinal crypt architecture, increased cellular proliferation and rates of cell migration, decreased apoptosis and development of adenomas and adenocarcinomas in the small and large intestine and the rectum.