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CircCDK14 Promotes Tumor Progression and Resists Ferroptosis in Glioma by Regulating PDGFRA.

ABSTRACT: CircRNAs have garnered significant interest in recent years due to their regulation in human tumorigenesis, yet, the function of most glioma-related circRNAs remains unclear. In this study, using RNA-Seq, we screened differentially regulated circRNAs in glioma, in comparison to non-tumor brain tissue. Loss- and gain-of-function strategies were used to assess the effect of circCDK14 on tumor progression both in vitro and in vivo. Luciferase reporter, RNA pull-down and fluorescence in situ hybridization assays were carried out to validate interactions between circCDK14 and miR-3938 as well as miR-3938 and PDGFRA. Transmission electron microscopic observation of mitochondria, iron and reactive oxygen species assays were employed for the detection of circCDK14 effect on glioma cells' sensitivity to erastin-induced ferroptosis (Fp). Our findings indicated that circCDK14 was overexpressed in glioma tissues and cell lines, and elevated levels of circCDK14 induced poor prognosis of glioma patients. CircCDK14 promotes the migration, invasion and proliferation of glioma cells in vitro as well as tumorigenesis in vivo. An evaluation of the underlying mechanism revealed that circCDK14 sponged miR-3938 to upregulate oncogenic gene PDGFRA expression. Moreover, we also found that circCDK14 reduced glioma cells' sensitivity to Fp by regulating PDGFRA expression. In conclusion, circCDK14 induces tumor in glioma and increases malignant tumor behavior via the miR-3938/PDGFRA axis. Hence, the miR-3938/PDGFRA axis may be an excellent candidate of anti-glioma therapy.

SUBMITTER: Chen S

PROVIDER: S-EPMC8741855 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glioma is one of the most deadly types of brain cancer. As it is highly invasive, the prognosis for glioma patients remains dismal, with median survival rarely exceeding 16 months. Thus, developing a new prognostic biomarker for glioma and investigating its molecular mechanisms is necessary for the development of an efficient treatment strategy. In this study, we analyzed a cohort of 1,131 glioma patients using RNA-seq data from The Cancer Genome Atlas (TCGA project) and Gene Expression Omnibus (GSE4290 and GSE16011 datasets), and validated the results using the RNA-seq data of 1,018 gliomas from the Chinese Glioma Genome Atlas (CGGA project). We used the R language as the main tool for statistical analysis and data visualization. We found that NCAPG, a mitosis-associated chromosomal condensing protein, is highly expressed in glioma tissues. Furthermore, the expression of NCAPG increased significantly with the increase in tumor grade, and high NCAPG expression was found to be a predictor of poor overall survival in glioma patients (P < 0.001). This result shows that NCAPG expression could be an independent prognostic factor. Importantly, when the expression of NCAPG was knocked down, the CCK-8 assay revealed that the proliferation of glioma cells (LN-229 and T98G cell lines) decreased significantly compared with the control group. In addition, the healing rates of these cells were significantly lower in the si-NCAPG group than in the control group (P < 0.001). We then used the CIBERSORT algorithm to analyze the expression levels of 22 subpopulations of immune cells and found that NCAPG was significantly negatively correlated with natural killer cell activation. In addition, it was positively correlated with MHC-I molecules and ADAM17. Our study is first in comprehensively describing the high expression of NCAPG in glioma. It also shows that NCAPG can function as an independent prognostic predictor of glioma, and that targeting NCAPG can be a new strategy for the treatment of glioma patients.

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CircCDK14 Promotes Tumor Progression and Resists Ferroptosis in Glioma by Regulating PDGFRA.

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