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MicroRNA-200c Increases Radiosensitivity of Human Cancer Cells with Activated EGFR-associated Signaling
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 김인아 | - |
dc.contributor.author | 구태률 | - |
dc.date.accessioned | 2018-05-28T16:59:52Z | - |
dc.date.available | 2018-05-28T16:59:52Z | - |
dc.date.issued | 2018-02 | - |
dc.identifier.other | 000000149680 | - |
dc.identifier.uri | https://hdl.handle.net/10371/141028 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의학과, 2018. 2. 김인아. | - |
dc.description.abstract | Introduction: A member of the microRNA-200 family, microRNA-200c (miR-200c), recently was found to have tumor-suppressive properties by inhibiting the epithelial-mesenchymal transition (EMT) process in several cancers. miR-200c also interacts with various cellular signaling molecules and regulates many important signaling pathways. In the present study, we investigated the radiosensitizing effect of miR-200c and its mechanism of radiosensitization in a panel of human cancer cell lines.
Methods: Malignant glioma (U251, T98G), breast cancer (MDA-MB-468), and lung carcinoma (A549) cell lines were transfected with control pre-microRNA, pre-miR-200c, or anti-miR-200c. Then, RT-PCR, clonogenic assays, immunoblotting, and immunocytochemistry were performed. To predict the potential targets of miR-200c, microRNA databases were used for bioinformatics analysis. Results: Bioinformatics analysis predicted that miR-200c may be associated with EGFR, AKT2, MAPK1, VEGFA, and HIF1AN. Ectopic overexpression of miR-200c downregulated p-EGFR, p-PI3K, p-AKT, and p-ERK and increased the radiosensitivity of U251, T98G, A549, and MDA-MB-468 cells. In contrast, miR-200c inhibition upregulated p-EGFR, p-PI3K, p-AKT, and p-ERK, and decreased radiation-induced cell killing. miR-200c led to persistent γH2AX focus formation and downregulated pDNA-PKc expression. Autophagy and apoptosis were major modes of cell death. We also confirmed that miR-200c downregulated the expression of VEGF, HIF-1α, and MMP2 in U251 and A549 cells. In these cells, overexpressing miR-200c inhibited invasion, migration, and vascular tube formation. These phenotypic changes were associated with E-cadherin and EphA2 downregulation and N-cadherin upregulation. miR-200c showed no observable cytotoxic effect on normal human fibroblasts and normal human astrocytes. Conclusions: miR-200c increased the cytotoxic effect of radiotherapy in a panel of human cancers with activated EGFR-associated signaling. The effects of miR-200c on the associated signaling molecules were indirectly confirmed with their phosphorylation levels. miR-200c also mitigated EMT-related processes. Taken together, our data suggest that miR-200c is an attractive target for improving the efficacy of radiotherapy via a unique modulation of the complex regulatory network controlling cancer pro-survival signaling and EMT. | - |
dc.description.tableofcontents | Introduction 1
Material and Methods 3 Results. 10 Discussion 32 References 37 Abstract in Korean 46 | - |
dc.format | application/pdf | - |
dc.format.extent | 1934409 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | microRNA-200c | - |
dc.subject | EGFR-associated signaling network | - |
dc.subject | radiosensitization | - |
dc.subject | human cancer cells | - |
dc.subject.ddc | 610 | - |
dc.title | MicroRNA-200c Increases Radiosensitivity of Human Cancer Cells with Activated EGFR-associated Signaling | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.contributor.affiliation | 의과대학 의학과 | - |
dc.date.awarded | 2018-02 | - |
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