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Identification of tumorigenesis related signaling pathways in the tumors with nuclear β-catenin overexpression
DC Field | Value | Language |
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dc.contributor.author | 박민희 | - |
dc.date.accessioned | 2017-07-07T16:10:47Z | - |
dc.date.available | 2017-07-07T16:10:47Z | - |
dc.date.issued | 2016 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/148870 | - |
dc.description | 의과대학/박사 | - |
dc.description.abstract | Mutations of β-catenin, CTNNB1, have been reported in various cancers, including colorectal cancer, breast cancer and lung cancer. Most β-catenin mutations are located in exon 3 of β-catenin genes, which lead to stabilization of β-catenin by blocking the destruction complex of β-catenin. In colorectal cancers, APC mutations are detected in 70-80% of colon cancers and β-catenin mutations are mutually exclusive and detected in about 5% of the colorectal cancers. Although the involvement of APC mutations in the altered Wnt/β-catenin pathway activity is well documented, the functional relevance between the deregulated Wnt/β-catenin signaling pathway and β-catenin mutations has not yet been fully understood in colon cancers. Also, the molecular significances of β-catenin mutations in the other cancers are not fully understood. Unlike colorectal carcinomas, nearly all of solid-pseudopapillary neoplasm (SPN) exhibit somatic mutation in exon3 of β-catenin, which results in abnormal nuclear accumulation (overexpression) of β-catenin. Although β-catenin mutation and activation of the Wnt/β-catenin signaling pathway have been implicated in the pathogenesis of SPN, the molecular regulatory networks remain poorly understood. To identify the altered pathways by nuclear overexpression of β-catenin in tumors, colon cancer and SPN were selected as study models. β-catenin mutation is responsible for the development of a small subset of colon cancers, while development of SPN is solely driven by β-catenin mutation. The molecular significances of nuclear β-catenin overexpression were compared in colon cancer as a model of nuclear β-catenin overexpression by altered genes involved in β-catenin degradation, and SPN as a model of nuclear β-catenin overexpression by β-catenin mutation. Since nuclear β-catenin shows heterogeneous expressions in colon cancers, the colorectal tumors were classified by percentage of nuclear β-catenin and identified a subset of colon cancers by comparing gene expression profiles in the colon cancers showing heterogeneous expression of nuclear β-catenin. As a result, it was found that overexpressed nuclear β-catenin activates genes involved in Wnt/β-catenin signaling, Notch signaling, Hedgehog signaling and ECM-receptor interaction in colon cancer. To identify gene subsets associated with nuclear β-catenin overexpression by β-catenin mutation, mRNA expression profiles of SPN and other pancreatic tumors (pancreatic adenocarcinomas and neuroendocrine tumors) were performed. All SPNs harbor β-catenin mutation, while the other pancreatic tumors harbor no β-catenin mutation. Unsupervised clustering analysis of mRNA expression distinguished SPNs as a distinct type of pancreatic tumor. Analysis of differentially expressed genes in SPN demonstrated that genes involved in Wnt/β-catenin, Hedgehog and androgen receptor signaling pathways as well as epithelial-mesenchymal transition were activated in solid-pseudopapillary neoplasms. Finally, the altered expression level of genes involved in three activated signaling pathways was confirmed by using cells transfected with β-catenin constructs. Transfection of mutant β-catenin constructs resulted in the translocation of androgen receptor into the nucleus and up-regulated several molecules involved in Wnt/β-catenin, Notch and Hedgehog signaling. In conclusion, overexpression of nuclear β-catenin commonly or selectively affects the signaling pathways of the Wnt/β-catenin, Notch, Hedgehog and androgen receptor, and contributes to the tumorigenesis of colon cancers and SPN. | - |
dc.description.statementOfResponsibility | open | - |
dc.publisher | Graduate School, Yonsei University | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.title | Identification of tumorigenesis related signaling pathways in the tumors with nuclear β-catenin overexpression | - |
dc.type | Thesis | - |
dc.contributor.alternativeName | Park, Minhee | - |
dc.type.local | Dissertation | - |
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