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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 胡孟君(Meng-Chun Hu) | |
dc.contributor.author | Chia-Hsin Chang | en |
dc.contributor.author | 張家心 | zh_TW |
dc.date.accessioned | 2021-05-11T04:50:19Z | - |
dc.date.available | 2019-08-27 | |
dc.date.available | 2021-05-11T04:50:19Z | - |
dc.date.copyright | 2019-08-27 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-16 | |
dc.identifier.citation | 1. World Health Organization (WHO) ; Breast cancer; 2019. [https://www.who.int/cancer/prevention/diagnosis-screening/breast-cancer/en/]
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/handle/123456789/630 | - |
dc.description.abstract | Liver receptor homolog-1 (LRH-1) 為細胞核受器之5A家族的成員,可參與類固醇生成及肝臟之膽酸恆定與醣類代謝等生理作用。LRH-1亦表現於乳癌細胞,可促進細胞增生及疾病進程。過去的文獻指出LRH-1在肝臟可表現全長之LRH-1 (LRH-1v1),於乳癌細胞則主要表現長度較短的異構物 (LRH-1v4),可能是由不同的啟動子調控,但其詳細的調控機制尚未釐清。本篇研究便深入探討LRH-1於乳癌細胞的轉錄調控。我們建構了2.7k之LRH-1v1啟動子 (啟動子I) 及LRH-1v4潛在的啟動子 (啟動子II),分析在人類肝癌細胞株HepG2與乳癌細胞株MCF7、T47D及MDA-MB-231的轉錄活性。結果顯示啟動子I於HepG2可表現很高的轉錄活性,然而於乳癌細胞則幾乎沒有活性。相反的,啟動子II於肝臟無活性表現,在乳癌細胞卻可表現轉錄活性。接著我們分析不同長度的啟動子II於乳癌細胞之活性,發現0.2k啟動子II即可於乳癌細胞表現很強的活性。在此區間內我們找到三個轉錄因子的關鍵結合序列,分別是細胞核受器常見的結合序列AGGTCA (NR)、specificity protein 1 (Sp1) 及specificity protein 3 (Sp3)。將三者之關鍵序列突變後,我們發現Sp1結合位的突變會降低啟動子II的轉錄活性,NR與Sp3結合位的突變則無影響。給予Sp1抑制劑mithramycin A可顯著降低啟動子II的活性,也會抑制乳癌細胞LRH-1v4的mRNA表現量。已知麩醯胺酸 (glutamine) 對於癌細胞能量來源與細胞增生扮演重要的角色,以shRNA抑制LRH-1表現後,發現許多麩醯胺酸代謝相關的基因於MCF7及MDA-MB-231皆顯著降低表現。綜合以上結果,本篇論文發現LRH-1於乳癌細胞可藉由啟動子II調控,表現LRH-1v4;且Sp1對啟動子II的活性很重要。此外,我們發現LRH-1可能影響乳癌細胞中麩醯胺酸的代謝。 | zh_TW |
dc.description.abstract | Liver receptor homolog-1 (LRH-1), a member of nuclear receptor 5A subfamily (NR5A), regulates steroidogenesis, and involves in bile-acid homeostasis and glucose metabolism in liver. LRH-1 also expresses in breast cancer cells, promoting cell proliferation and progression of cancer cells. Previous studies showed that LRH-1 expresses a full-length isoform (LRH-1v1) in liver cells, whereas a shorter isoform (LRH-1v4) is predominantly present in breast cancer cells, which may be regulated by different promoters. The detail of regulating mechanism of LRH-1 expression in breast cancer cells is unclear. In this study, we aim to investigate the transcriptional regulation of LRH-1 in breast cancer cells. We constructed a 2.7 kb DNA fragment from LRH-1v1 promoter I and the potential promoter of LRH-1v4 isoform (promoter II) to analyze their transcriptional activities in human hepatocellular carcinoma (HepG2) and breast cancer cell lines (MCF7, T47D, and MDA-MB-231). Our data reveal that promoter I expresses high activity in HepG2; however, the activity of promoter I was not detected in breast cancer cells. In contrast, the transcriptional activity of promoter II was apparently detected in breast cancer cells but not observed in HepG2. The promoter II deletion analysis showed that the length of 0.2 kb sequence of promoter II had highest activity in breast cancer cells. Three potential binding sequences for nuclear receptor (AGGTCA , NR), specificity protein 1 (Sp1), and specificity protein 3 (Sp3) were predicted on 0.2 kb promoter II. Mutation of the Sp1 binding site significantly reduced the activity of promoter II, while mutation of NR and Sp3 binding sites had no effect on promoter II activity. In addition, treatment with Sp1 inhibitor mithramycin A significantly reduces activity of promoter II and also down-regulated levels of LRH-1v4 mRNA in breast cancer cells. Glutamine plays a critical role in energy generation and cancer cells proliferation. We found that knockdown of LRH-1 decreased mRNA levels of several genes involved in glutamine metabolism in breast cancer cells. Overall, our study demonstrated that LRH-1 is potentially regulated by promoter II to express LRH-1v4 in breast cancer cells. Sp1 positively regulates the activity of promoter II. Beside, LRH-1 may involve in process of glutamine metabolism in breast cancer cells. | en |
dc.description.provenance | Made available in DSpace on 2021-05-11T04:50:19Z (GMT). No. of bitstreams: 1 ntu-108-R06441009-1.pdf: 2682541 bytes, checksum: a0be0073d6a327cd16e1a31c9b2ce7f5 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 誌謝 I
目錄 II 表次 IV 圖次 V 摘要 VI Abstract VII 第一章 序論 1 一、 乳癌簡介 1 1. 概況 1 2. 分類 1 二、 LRH-1的生理功能 2 三、 LRH-1的結構與調控 4 1. LRH-1的結構 4 2. LRH-1的異構物 5 3. 轉譯後修飾 6 4. 輔助調節因子 6 四、 LRH-1於癌症的作用 8 五、 研究目的 10 第二章 材料與方法 11 一、 細胞培養 11 二、 藥品 12 三、 質體 12 四、 定點突變聚合酶連鎖反應 (site-directed mutagenesis) 16 五、 蛋白質萃取 17 六、 西方墨點法 (Western blot) 18 七、 RNA萃取 20 八、 即時性反轉錄聚合酶連鎖反應 (real-time RT-PCR) 21 九、 冷光酵素活性分析 (Luciferase assay) 23 十、 shRNA knockdown 24 十一、 統計分析 (statistical analysis) 26 第三章 結果 27 一、 LRH-1於乳癌細胞的表現 27 二、 LRH-1啟動子II於乳癌細胞表現轉錄活性 28 三、 Sp1參與LRH-1之調控 29 四、 E2及PGE2於乳癌細胞對LRH-1表現的影響 30 五、 LRH-1於乳癌細胞對麩醯胺酸代謝的影響 31 第四章 討論 32 一、 LRH-1於乳癌細胞之表現 32 二、 LRH-1的啟動子 33 三、 LRH-1於乳癌細胞的調控 34 四、 LRH-1對麩醯胺酸代謝的影響 35 參考文獻 38 | |
dc.language.iso | zh-TW | |
dc.title | Liver receptor homolog-1 (LRH-1) 於乳癌細胞的轉錄調控 | zh_TW |
dc.title | Transcriptional regulation of liver receptor homolog-1 (LRH-1) in breast cancer cells | en |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 徐立中(Li-Chung Hsu),張淑芬(Shwu-Fen Chang),盧主欽(Juu-Chin Lu) | |
dc.subject.keyword | LRH-1,乳癌細胞,Sp1,麩醯胺酸代謝, | zh_TW |
dc.subject.keyword | LRH-1,breast cancer cells,Sp1,glutamine metabolism, | en |
dc.relation.page | 62 | |
dc.identifier.doi | 10.6342/NTU201903809 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2019-08-16 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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