title: Genome-wide identification of TCF7L2/TCF4 target miRNAs reveals a role for miR-21 in Wnt-driven epithelial cancer.
abstract: 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 β-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 β-catenin/TCF4 signaling.
authors.affiliation: Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin 300052, PR China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Lan
authors.forename: Xiao
authors.initials: X
authors.lastname: Yue
authors.forename: Lei
authors.initials: L
authors.lastname: Han
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Shi
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Peiyu
authors.initials: P
authors.lastname: Pu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Kang
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D055106:Genome-Wide Association Study; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D049410:Luciferases, Renilla