Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors.
Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors.
复制标题
DOI：
10.1158/0008-5472.166.65.1
复制
发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
T. Reichling;K. Goss;D. Carson;R. Holdcraft;Cathy Ley-Ebert;D. Witte;B. Aronow;J. Groden
中科院分区：
文献类型：
--
作者：
T. Reichling;K. Goss;D. Carson;R. Holdcraft;Cathy Ley-Ebert;D. Witte;B. Aronow;J. Groden
结肠腺瘤性息肉病(APC)抑癌基因是正常肠上皮细胞Wnt信号通路的主要调节因子。APC与Axin和GSK-3β一起形成了降解β-连环蛋白所必需的复合体，从而阻止了β-连环蛋白/T细胞因子的相互作用和生长控制基因如c-myc和细胞周期蛋白d1的改变。通过APC/APC突变导致Wnt通路的不适当激活，导致小鼠和人类胃肠道肿瘤的形成。为了发现可能促进胃肠道肿瘤进展的新基因，我们使用基因芯片技术鉴定了114个在APC(Min)小鼠十二指肠、空肠和结肠腺瘤中表达水平改变的基因。在小鼠胚胎发育的16.5天、出生后1天或出生后14天(相对于正常成人肠道)，这114个基因中的24个的表达没有变化。这24个基因是以前未知的Wnt靶点。其中7个基因通过实时逆转录-聚合酶链式反应得到验证，4个基因通过与小鼠腺瘤的原位杂交得到验证。实时逆转录-聚合酶链式反应分析发现，6个基因Igfbp5、Lcn2、Ly6d、N4wbp4(PMEPA1)、S100c和Sox4的表达水平也发生了变化。
The adenomatous polyposis coli (APC) tumor suppressor is a major regulator of the Wnt signaling pathway in normal intestinal epithelium. APC, in conjunction with AXIN and GSK-3beta, forms a complex necessary for the degradation of beta-catenin, thereby preventing beta-catenin/T-cell factor interaction and alteration of growth-controlling genes such as c-MYC and cyclin D1. Inappropriate activation of the Wnt pathway, via Apc/APC mutation, leads to gastrointestinal tumor formation in both the mouse and human. In order to discover novel genes that may contribute to tumor progression in the gastrointestinal tract, we used cDNA microarrays to identify 114 genes with altered levels of expression in Apc(Min) mouse adenomas from the duodenum, jejunum, and colon. Changes in the expression of 24 of these 114 genes were not observed during mouse development at embryonic day 16.5, postnatal day 1, or postnatal day 14 (relative to normal adult intestine). These 24 genes are not previously known Wnt targets. Seven genes were validated by real-time reverse transcription-PCR analysis, whereas four genes were validated by in situ hybridization to mouse adenomas. Real-time reverse transcription-PCR analysis of human colorectal cancer cell lines and adenocarcinomas revealed that altered expression levels were also observed for six of the genes Igfbp5, Lcn2, Ly6d, N4wbp4 (PMEPA1), S100c, and Sox4.