Abstract
Glioma is the most common malignant tumor in adult brain characteristic with poor prognosis and low survival rate. Despite the application of advanced surgery, chemotherapy, and radiotherapy, the patients with glioma suffer poor treatment effects due to the complex molecular mechanisms of pathological process. In this paper, we conducted the experiments to prove the critical roles TET1 played in glioma and explored the downstream targets of TET1 in order to provide a novel theoretical basis for clinical glioma therapy. RT-qPCR was adopted to detect the RNA level of TET1 and β-catenin; Western blot was taken to determine the expression of proteins. CCK8 assay was used to detect the proliferation of glioma cells. Flow cytometry was used to test cell apoptosis and distribution of cell cycle. To detect the migration and invasion of glioma cells, wound healing assay and Transwell were performed. It was found that downregulation of TET1 could promote the proliferation migration and invasion of glioma cells and the concomitant upregulation of β-catenin, and its downstream targets like cyclinD1 and c-myc were observed. The further rescue experiments were performed, wherein downregulation of β-catenin markedly decreases glioma cell proliferation in vitro and in vivo. This study confirmed the tumor suppressive function of TET1 and illustrated the underlying molecular mechanisms regulated by TET1 in glioma.
Highlights
As shown in previous studies, modification of DNA plays critical roles in cell proliferation, apoptosis, tumorigenesis, and metastasis [1, 2]
The results showed the lower expression of TET1 in tumor tissues compared with adjacent normal tissues (Figure 1(a))
A previous study determined that TET1 acted as a tumor suppressor in nasopharyngeal carcinoma via antagonizing Wnt/β-catenin pathway [14].Corresponding with previous research, our work identified that downregulation of TET1 could increase the expression of key proteins of Wnt/β-catenin including β-catenin and phosphorylated GSK3β and the underlying targets of Wnt pathway such as cyclinD1 and c-myc (Figures 6(a)–6(c))
Summary
As shown in previous studies, modification of DNA plays critical roles in cell proliferation, apoptosis, tumorigenesis, and metastasis [1, 2]. Modification of DNA plays critical roles in cell proliferation, apoptosis, tumorigenesis, and metastasis [1, 2]. Methylation at 5-position of cytosine (5mC) is the most common DNA modification in CpG dinucleotide which has regulatory function on expression of genes and genomic stability [3, 4]. Expression level of 5hmC plays critical roles on neurogenesis, differentiation, and neurodevelopment in embryonic phase and adults. Kim et al determined that overexpression of TET1 promotes neurogenesis ahead of time during the development of fetal brain in mice [9]. Li et al prove that overexpression of TET2 in the hippocampus of mature adults can enhance the expression of 5hmC and promote the neurogenesis in hippocampus which is declined by ageing and improve the ability of learning and memory [10]
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