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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.
International Journal of Oncology 09/2011; 40(2):519-26. · 2.40 Impact Factor
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09/2011; , ISBN: 978-953-307-280-7
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Fengming Lan,
Xiao Yue,
Lei Han,
Xubo Yuan,
Zhendong Shi,
Kai Huang,
Yang Yang,
Jian Zou,
Junxia Zhang,
Tao Jiang,
Peiyu Pu,
Chunsheng Kang
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ABSTRACT: The goal in this study was to investigate the antitumor effect of aspirin in glioblastoma cells and the molecular mechanism involved in its antineoplastic activities.
The authors used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, flow cytometry, the annexin V method, and Transwell cell invasion test to detect the proliferation and invasive activity of U87 and A172 glioma cells before and after being treated with aspirin. To determine the effects of aspirin on β-catenin/T-cell factor (TCF) transcription activity, reporter constructs containing 3 repeats of the wild-type (TOPflash) or mutant (FOPflash) TCF-binding sites were used. Reverse transcriptase polymerase chain reaction and Western blot analyses were used to detect the expression of multiple β-catenin/TCF target genes following aspirin treatment.
The transcriptional activity of the β-catenin/TCF complex was strongly inhibited by aspirin. Increasing the concentration of aspirin resulted in decreased expression of c-myc, cyclin D1, and fra-1 mRNA and protein in U87 and A172 cells in a dose-dependent manner. Aspirin inhibited glioma cell proliferation and invasive ability, and induced apoptotic cell death.
The results suggest that aspirin is a potent antitumor agent, and that it exerts its antineoplastic action by inhibition of the β-catenin/TCF signaling pathway in glioma cells.
Journal of Neurosurgery 07/2011; 115(4):780-8. · 2.96 Impact Factor
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Xiao Yue, FengMing Lan,
WeiDong Yang,
Yang Yang,
Lei Han,
AnLing Zhang,
JiLong Liu,
HuaZong Zeng,
Tao Jiang,
PeiYu Pu,
ChunSheng Kang
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ABSTRACT: Malignant gliomas are the most common type of intrinsic central nervous system (CNS) tumors with high mortality and morbidity. β-catenin is overexpressed in human glioblastoma and knockdown of β-catenin inhibits glioblastoma cell proliferation and invasive ability, and induces apoptotic cell death. Furthermore, treating the nude mice carrying established subcutaneous LN229 gliomas with siRNA targeting β-catenin intratumorally also delayed the tumor growth. However, the mechanisms of down-regulation of β-catenin that represses glioblastoma malignancy behavior remain to be elucidated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the β-catenin biologic association network, and identified several interactions of this network with the EGFR pathway. In both in vitro and in vivo studies, our results confirmed down-regulation of β-catenin induced reduced expression of EGFR, STAT3 and AKT1 mRNA and protein, besides, the level of phosphorylated Akt also decreased. A similar reduction in expression of CyclinD1, MMP2 and MMP9, downstream genes of the EGFR pathway, was observed. These results suggest that the Wnt/β-catenin pathway regulates glioma cell proliferation and invasion, in part via the EGFR pathway.
Brain research 10/2010; 1366:27-37. · 2.46 Impact Factor
