Novel candidate targets of beta-catenin/T-cell factor signaling identified by gene expression profiling of ovarian endometrioid adenocarcinomas.
Novel candidate targets of beta-catenin/T-cell factor signaling identified by gene expression profiling of ovarian endometrioid adenocarcinomas.
复制标题
DOI：
--
复制
发表时间：
2003-06
期刊：
影响因子：
11.2
通讯作者：
D. Schwartz;R. Wu;S. Kardia;A. Levin;Chiang-Ching Huang;K. Shedden;R. Kuick;David E. Misek
中科院分区：
文献类型：
--
作者：
D. Schwartz;R. Wu;S. Kardia;A. Levin;Chiang-Ching Huang;K. Shedden;R. Kuick;David E. Misek
β-连环蛋白（β-cat）是Wnt信号通路的关键组分，其活性在约40%的卵巢类囊腺癌（OEAs）中失调，通常是CTNNB 1基因突变的结果。β-cat在肿瘤转化中的功能依赖于T细胞因子（TCF）转录因子，但在OEAs和其他Wnt通路缺陷的癌症中，β-cat与TCF相互作用激活的特定基因在很大程度上尚不清楚。作为一种策略，以确定β-cat/TCF转录目标可能有助于OEA的发病机制，我们使用寡核苷酸微阵列比较基因表达在原发性OEAs与β-cat的调节突变缺陷（n = 11）与OEAs与完整的β-cat活性的调节（n = 17）。基于全局基因表达的层次聚类和主成分分析将β-cat缺陷型肿瘤与具有完整β-cat调节的肿瘤区分开。我们通过选择在β-cat缺陷型肿瘤中的表达比β-cat调节完整型肿瘤中的表达增加至少2倍且在t检验中具有显著性（P < 0.05）的基因，鉴定了81个潜在的β-cat/TCF靶点。81个基因中的7个先前已被报道为Wnt/β-cat途径靶标（即，BMP 4、CCND 1、CD 44、FGF 9、EPHB 3、MMP 7和MSX 2）。几个已知的和候选的目标基因在OEAs的差异表达得到证实。对于候选靶基因CST 1和EDN 3，报告基因和染色质免疫沉淀分析直接涉及β-cat和TCF在其调控中。81个候选基因中有67个的推定调控元件的分析显示，与对照基因中的模式相比，共有TCF结合位点的位置和丰度存在明显差异。我们的研究结果意味着，分析原发性肿瘤样本的基因表达谱数据，注释详细的分子信息可能是一个强大的方法，以确定在癌细胞中有缺陷的信号通路的关键下游目标。
The activity of beta-catenin (beta-cat), a key component of the Wnt signaling pathway, is deregulated in about 40% of ovarian endometrioid adenocarcinomas (OEAs), usually as a result of CTNNB1 gene mutations. The function of beta-cat in neoplastic transformation is dependent on T-cell factor (TCF) transcription factors, but specific genes activated by the interaction of beta-cat with TCFs in OEAs and other cancers with Wnt pathway defects are largely unclear. As a strategy to identify beta-cat/TCF transcriptional targets likely to contribute to OEA pathogenesis, we used oligonucleotide microarrays to compare gene expression in primary OEAs with mutational defects in beta-cat regulation (n = 11) to OEAs with intact regulation of beta-cat activity (n = 17). Both hierarchical clustering and principal component analysis based on global gene expression distinguished beta-cat-defective tumors from those with intact beta-cat regulation. We identified 81 potential beta-cat/TCF targets by selecting genes with at least 2-fold increased expression in beta-cat-defective versus beta-cat regulation-intact tumors and significance in a t test (P < 0.05). Seven of the 81 genes have been previously reported as Wnt/beta-cat pathway targets (i.e., BMP4, CCND1, CD44, FGF9, EPHB3, MMP7, and MSX2). Differential expression of several known and candidate target genes in the OEAs was confirmed. For the candidate target genes CST1 and EDN3, reporter and chromatin immunoprecipitation assays directly implicated beta-cat and TCF in their regulation. Analysis of presumptive regulatory elements in 67 of the 81 candidate genes for which complete genomic sequence data were available revealed an apparent difference in the location and abundance of consensus TCF-binding sites compared with the patterns seen in control genes. Our findings imply that analysis of gene expression profiling data from primary tumor samples annotated with detailed molecular information may be a powerful approach to identify key downstream targets of signaling pathways defective in cancer cells.