| Gliomas are the most common primary brain tumors, accounting for more than70%of all primary central nervous system (CNS) neoplasms. Though Current therapies for GBMs include surgery, radiotherapy, and chemotherapy,the grade IV glioma, glioblastoma, with a median survival of1year, has one of the worst prognoses among all types of human tumors. Disappointing results in the improvement of prognosis over the last30years have fueled investigation into mechanisms involved in the progression of glioblastoma and new treatment strategies. The past decades, advances in the fields of molecular biology and cellular biology, as well as genomics, have begun to improve our understanding of malignant gliomas.Beta-catenin/TCF pathway is abnormally activated in various tumors. At the same time, increasing evidences suggest that aberrant activation of Wnt/(3-catenin signaling is involved in glioma development and progression. Activation of Wnt signaling inhibits β-catenin phosphorylation and hence its degradation. The elevation of β-catenin levels leads to its nuclear accumulation and complex formation with LEF/TCF transcription factors. Transcription factor7like2(TCF7L2, also called and hereafter referred to as TCF4) is a76kDa protein encoded by a single exon. The N-terminal53amino acids of TCF4bind with high affinity to β-catenin, forming the TCF/β-catenin transcription complex that regulates transcriptional responses to Wnt signaling. Aberrant activation of Wnt signaling results in a transcriptional profile in human cancer cells similar to that found in cells physiologically driven by TCF/β-catenin As such, TCF4chromatin occupancy appears to function both as a developmental transcription factor necessary for progenitor cell development and as the primary transforming factor in human tumors such as colorectal cancer.MiRNA have been implicated in the pathogenesis of several human diseases, such as neurodegenerative disorders, diabetes and more recently in viral and metabolic diseases. In recent years, miRNAs have been identified in the progression of various cancers and proposed as novel targets for anticancer therapies. Although miRNAs are key regulators of gene expression in both normal human physiology and disease, and thousands of microRNAs have been identified in organisms from viruses to primates through cloning and sequencing, or computational prediction based on strong conservation of miRNA sequence motifs, the transcriptional regulation of miRNA are poorly understood.In the present study, we demonstrated that Genome-wide identification of TCF7L2/TCF4target miRNA reveals a role for miR-21in Wnt-driven epithelial cancer. This research departs into the following three parts:The first part:Identification of putative TCF4peaks within10kb of miRNA genes though TCF4peak analyses and ChlP-PCR.The second part:Antitumor effect of aspirin in glioblastoma cells by modulation of beta-catenin/T-cell factor-mediated transcriptional activity.The third part:TCF4activates miR-21transcription by directly binding to its promoter. |
