Genome-wide identification of TCF7L2/TCF4 target miRNAs reveals a role for miR-21 in Wnt-driven epithelial cancer
Genome-wide identification of TCF7L2/TCF4 target miRNAs reveals a role for miR-21 in Wnt-driven epithelial cancer
复制标题
TCF7L2/TCF4 靶 miRNA 的全基因组鉴定揭示了 miR-21 在 Wnt 驱动的上皮癌中的作用
DOI：
10.3892/ijo.2011.1215
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发表时间：
2012-02-01
影响因子：
5.2
通讯作者：
Kang, Chunsheng
中科院分区：
文献类型：
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作者：
Lan, Fengming;Yue, Xiao;Kang, Chunsheng
转录因子7样2（TCF 7 L2，也称为TCF 4）是一种Wnt信号通路转录因子，参与调节许多Wnt靶向基因。最近，在LS 174 T中报道了数千个高置信度的TCF 4结合位点。然而，在结肠癌细胞中，潜在的TCF 4靶向miRNA仍然在很大程度上未知。在此，我们利用生物信息学方法，在TCF 4染色质占据位点附近发现了26个miRNA转录起始位点（TSS），并通过ChIP-PCR验证了这些位点在LS 174 T结肠癌细胞、MCF-7乳腺癌细胞和U87胶质瘤细胞中是真正的TCF 4靶点。然后，我们选择了miR-21，以首次证明TCF 4通过与启动子区结合直接激活miRNA的转录。组织阵列分析支持这一发现，揭示了β-连环蛋白通路的激活和miR-21的原位表达之间的正相关性。最后，基于阿司匹林对结直肠癌发病率和死亡率的众所周知但知之甚少的预防作用，我们报告了阿司匹林给药后miR-21的下调。总之，我们的研究结果确定了TCF 4对miR-21的直接转录调控，并表明miR-21在激活β-连环蛋白/TCF 4信号传导后在癌细胞增殖和侵袭中的作用。
Transcription factor 7 like 2 (TCF7L2, also known as TCF4) is a Wnt signaling pathway transcription factor involved in regulation of numerous Wnt targeted genes. Recently, thousands of high-confidence TCF4 binding sites were reported in LS174T. colon carcinoma cells, however, potential TCF4 target miRNAs remain largely unknown. Here, we utilized a bioinformatics approach to discover 26 miRNA transcription start sites (TSSs) within close proximity to TCF4 chromatin occupancy sites, and validated these sites as bona fide TCF4 targets in LS174T colon carcinoma cells, MCF-7 breast cancer cells and U87 glioma cells by ChIP-PCR. We then selected miR-21 to demonstrate for the first time direct TCF4 transcriptional activation of a miRNA via binding to the promoter region. Tissue array analysis supported this finding, revealing a positive correlation between activation of the beta-catenin pathway and in situ expression of miR-21. Finally, based upon the well known but poorly understood preventive effect of aspirin on colorectal cancer incidence and mortality, we report downregulation of miR-21 upon administration of aspirin. In sum, our findings identify direct transcriptional regulation of miR-21 by TCF4 and suggest a role for miR-21 in cancer cell proliferation and invasion upon activation of beta-catenin/TCF4 signaling.