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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃敏銓,林凱信 | |
| dc.contributor.author | Wan-Ling Ho | en |
| dc.contributor.author | 何宛玲 | zh_TW |
| dc.date.accessioned | 2021-06-16T03:37:55Z | - |
| dc.date.available | 2015-09-25 | |
| dc.date.copyright | 2015-09-25 | |
| dc.date.issued | 2015 | |
| dc.date.submitted | 2015-04-13 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/54757 | - |
| dc.description.abstract | 簡單黏蛋白型醣類抗原例如Tn、T、唾液酸-Tn (sTn)、和唾液酸-T (sT) 抗原的異常表現被認為與惡性轉化及癌症病程惡化有關聯性。黏蛋白型O型醣化起始於把N-acetylgalactosamine (即N-乙醯胺基半乳糖，簡稱GalNAc) 從UDP-Gal NAc轉移到目標蛋白的絲胺酸 (serine) 和蘇胺酸 (threonine) 上，進而形成 Tn抗原；這個反應是由N-乙醯胺基半乳糖轉移酶家族 (GalNAc transferases；簡稱GALNTs) 所催化，是一個重要的調控步驟。其中的一員GALNT2 在小鼠胚胎形成過程當中的神經組織有具差別性的表現形態。Tn抗原再接上Gal後，便形成了 core 1，也就是 T 抗原。β1,3-乙醯葡萄糖胺轉移酶家族 (β1,3-N-acetylglucosaminyltransferases；簡稱B3GNT) 參與了core 1 到 core 4 的形成或延長，其中B3GNT3，幾乎單獨地負責把GlcNAc以β1-3 linkage鍵結的方式加到core 1 (T抗原) 上，形成 extended core 1。因此我們研究的主題是探討這兩個醣基轉移酶 (B3GNT3 及 GALNT2) 在人類神經母細胞瘤所扮演的角色。在B3GNT3的研究中，我們利用免疫組織學的方法，發現在愈分化成熟的神經母細胞中，B3GNT3 的表現量及免疫染色強度愈強。另外，B3GNT3 的表現在臨床病理與生物學因子的統計方面，除了與組織分化的程度有相關性外，也與 Shimada 組織學分類屬較佳預後者及較可能存活者，有顯著關聯性。多變項存活分析則發現，與”較早的臨床分期”、”MYCN 無擴增現象” 並列為預後較佳 (五年存活率) 的獨立預後因子。在細胞惡性表現型的實驗中，我們發現 B3GNT3 會抑制神經母細胞的移行及侵犯行為，而且惡性表現型的改變是經由抑制 Akt 及 ERK 的活化所造成的，也解釋了B3GNT3 極有可能是經由細胞分化程度以外的機制，例如改變或修飾細胞表面的O型醣化，進而影響細胞移行及侵犯等惡性行為。在許多腫瘤細胞的行為中，Akt 及 ERK 是 integrins 和 receptor tyrosine kinases 的下游訊息傳遞分子，而之前也有研究顯示 integrins 和 receptor tyrosine kinases 帶有O型聚醣，因此我們認為 B3GNT3 也可能修飾神經母細胞上 integrins 或 receptor tyrosine kinases 的O型聚醣，形成了 extended core 1 的寡醣鏈，進而抑制了神經母細胞的惡性行為。在 GALNT2 的研究中，我們同樣先利用免疫組織學的方法發現，發現在愈分化成熟的神經母細胞中，GALNT2 的表現量及免疫染色強度愈強。另外，GALNT2 的表現在臨床病理與生物學因子的統計方面，與發病年紀較年輕、較早的臨床分期、原發部位為腎上腺以外的位置、國際神經母細胞瘤病理分類被歸類在預後較佳者、及 MYCN 無擴增現象等，有顯著的關聯性。多變項存活分析則顯示 GALNT2 的表現與其他變項 (較早的臨床分期、MYCN 無擴增現象者、國際神經母細胞瘤病理學分類被歸類在預後較佳者) 同為預後較佳 (五年存活率) 的獨立預後因子。神經母細胞瘤細胞經過 GALNT2 過度表現 (overexpression) 處理後會抑制類胰島素生長因子所誘導的細胞行為，包括細胞生長、移行、侵犯等惡性行為；然而，GALNT2減量 (knockdown) 則會促進這三種細胞惡性行為。此結果暗示著，GALNT2 (與B3GNT3 類似) 亦極有可能是經由細胞分化程度以外的機制，例如改變或修飾細胞表面受質的O型醣化，進而影響細胞移行及侵犯等惡性行為。進一步的機制探討則發現 GALNT2 過度表現會修飾類胰島素生長因子接受器上的O型醣化，進而抑制類胰島素生長因子接受器被類胰島素生長因子誘發的二聚體反應 (dimerization)，再影響下游的訊息傳遞。因此我們認為 GALNT2 會經由調控神經母細胞的類胰島素生長因子接受器之訊息傳遞，進而影響神經母細胞的癌症行為，也說明了它在神經母細胞瘤致病機轉所扮演的重要角色。我們認為雖然仍有許多相關的醣基轉移酶可能同時或有前後順序的影響著神經母細胞的行為，但這兩個醣基轉移酶的研究將有助於對神經母細胞腫瘤形成原因的了解，同時也可能有助於對神經母細胞瘤醣化作用標靶治療的發展。 | zh_TW |
| dc.description.abstract | Aberrant expression of the simple mucin-type carbohydrate antigens such as Tn, sialyl-Tn, T, and sialyl-T antigens is associated with malignant transformation and cancer progression. N-acetylgalactosaminyltransferase 2 (GALNT2), one of the enzymes that mediate the initial step of mucin-type O-glycosylation, is responsible for forming Tn antigen. GALNT2 is expressed differentially in nervous tissues during mouse embryogenesis. T synthase galactosylates Tn to form the core 1 (Galβ1→3GalNAc, T antigen). β1,3-N-acetylglucosaminyltransferase-3 (B3GNT3), formerly called core 1 β3GlcNAcT, is responsible for adding GlcNAc to core 1 (T antigen) in a β1,3 linkage, forming extended core 1 oligosaccharides. However, the roles of these two glycosyltransferases in neuroblastoma (NB) remain unclear. Here we showed that increased B3GNT3 expression evaluated by immunohistochemistry in NB tumor tissues correlated well with the histological grade of differentiation as well as a favorable Shimada’s subset of pathology. Multivariate analyses revealed that positive B3GNT3 expression in tumor tissues predicted a favorable prognosis in NB patients independent of other prognostic markers. B3GNT3 overexpression suppresses T antigen formation and malignant phenotypes including migration and invasion of SK-N-SH cells, whereas B3GNT3 knockdown enhances these phenotypes of SK-N-SH cells. Moreover, B3GNT3 expression decreased phosphorylation of focal adhesion kinase (FAK), Src, paxillin, Akt, and ERK1/2. On the other hand, we showed that increased GALNT2 expression evaluated using immunohistochemistry in NB tumor tissues correlated well with the histological grade of differentiation as well as younger age at diagnosis, early clinical stage, primary tumor originated from the extra-adrenal site, favorable INPC histology, and MYCN non-amplification. Multivariate analysis showed that GALNT2 expression is an independent prognostic factor for better survival for NB patients. GALNT2 overexpression suppressed IGF-1-induced cell growth, migration, and invasion of NB cells, whereas GALNT2 knockdown enhanced these NB phenotypes. Mechanistic investigations demonstrated that GALNT2 overexpression modified O-glycans on IGF-1R, which suppressed IGF-1-triggered IGF-1R dimerization and subsequent downstream signaling events. Conversely, these properties were reversed by GALNT2 knockdown in NB cells. Our findings suggest that GALNT2 regulates malignant phenotypes of NB cells through the IGF-1R signaling pathway, suggesting a critical role for GALNT2 in the pathogenesis of NB. These results regarding B3GNT3 and GALNT2 may also provide an alternative approach for cancer therapy by means of modulating cancer-specific glycosylation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T03:37:55Z (GMT). No. of bitstreams: 1 ntu-104-Q96421011-1.pdf: 3450811 bytes, checksum: ad1e17abe55cec99428f30fcfacfe148 (MD5) Previous issue date: 2015 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii 英文摘要 vi 博士論文內容 第一章 緒論 (Introduction) 1 1.1. 神經母細胞瘤 2 1.2. 蛋白質醣化 (Protein glycosylation) 4 1.3. N型醣化 4 1.4. O型醣化 5 1.5. 異常的O型醣化與癌症 7 1.6. 簡單黏蛋白型醣類抗原 7 1.7. B3GNT family及其與疾病的關係 8 1.8. GALNT family及其與疾病的關係 10 第二章 研究方法與材料 (Materials and Methods) 13 2.1. 病患資料及檢體收集 (Patients and tissue samples) 14 2.2. 免疫組織染色法 (Immunohistochemistry) 15 2.3. 細胞株及細胞培養 16 2.4. 細胞轉殖（Transfection） 17 2.5. B3GNT3及GALNT2 減量 (Knockdown of B3GNT3 and GALNT2) 18 2.6. 免疫螢光染色 (Immunofluorescent staining) 18 2.7. 細胞聚落形成試驗 (colony formation assay) 及噻唑藍比色法 (MTT assay) 19 2.8. 裸鼠的異種移植物模型 (Xenograft tumor growth in nude mice) 19 2.9. Transwell 移行以及Matrigel 侵犯試驗 20 2.10. 流式細胞儀 (Flow cytometry) 21 2.11. 西方印漬術及凝集素pull-down 試驗 22 2.12. 接受器二聚體試驗 (Receptor dimerization assay) 23 2.13. 統計分析 (Statistical analyses) 24 第三章 結果 (Results) 25 3.1. B3GNT3 及GALNT2在神經母細胞瘤的表現以及其與臨床病理和生物性因子的關聯性 26 3.2. B3GNT3 及GALNT2的表現與存活分析 28 3.3. B3GNT3 及 GALNT2 在神經母細胞的轉殖 29 3.4. B3GNT3 抑制神經母細胞的惡性表現型 (malignant phenotypes) 31 3.5. B3GNT3 是經由減少Akt及ERK的活性而抑制神經母細胞移行及侵犯能力 32 3.6. GALNT2 抑制神經母細胞的惡性表現型 (malignant phenotypes) 33 3.7. GALNT2 抑制小鼠神經母細胞瘤的生長 (GALNT2 inhibits tumor growth in vivo) 34 3.8. GALNT2 修飾神經母細胞 IGF-1R 的醣化作用及活性 34 3.9. GALNT2 調控神經母細胞上 IGF-1R 的磷酸化及下游的訊息傳遞 36 第四章 討論 (Discussion) 37 4.1. B3GNT3 38 4.2. GALNT2 43 第五章 展望 49 第六章 論文英文簡述 (Summary) 56 第七章 參考文獻 (References) 84 第八章 圖表 (Tables and Figures) 92 表 1. B3GNT3 在神經母細胞瘤的表現與臨床病理及生物學特徵的關聯性 93 表 2. GALNT2 在神經母細胞瘤的表現與臨床病理及生物學特徵的關聯性 94 表 3. 影響存活率的臨床病理和生物性因子之分析 (B3GNT3) 95 表 4. 影響存活率的臨床病理和生物性因子之分析 (GALNT2) 96 圖 1: 黏蛋白型O型聚醣的合成步驟 97 圖 2: 最常見的黏蛋白型O型聚醣合成途徑 98 圖 3: B3GNT3在神經母細胞瘤的表現 99 圖 4: GALNT2在神經母細胞瘤的表現 100 圖 5: B3GNT3的表現與病患的存活率有相關性 101 圖 6: GALNT2的表現與神經母細胞瘤的組織學分類及病患的存活率有相關性 102 圖 7: B3GNT3 對SK-N-SH細胞惡性表現型的影響 103 圖 8: B3GNT3 knockdown對SK-N-SH細胞惡性表現型的影響 104 圖 9: B3GNT3 所調控的訊息傳遞分子 105 圖 10: SH-SY5Y 和 SK-N-DZ 親代細胞表面Tn、T、sTn、及 sT 抗原的表現形態 106 圖 11: GALNT2 在神經母細胞的轉殖 107 圖 12: GALNT2 在神經母細胞的轉殖 108 圖 13: GALNT2 轉殖劑量與細胞表面 Tn 抗原表現量的相關性 109 圖 14: GALNT2 對神經母細胞惡性表現型的影響 110 圖 15: GALNT2 knockdown (使用GALNT2 siRNA 2號) 對SK-N-DZ細胞惡性表現型的影響 111 圖 16: GALNT2 會抑制小鼠腫瘤的生長 112 圖 17: GALNT2 對SK-N-AS細胞惡性表現型的影響 113 圖 18: 凝集素VVA 對 Tn 結構有特異性 114 圖 19: GALNT2 修飾神經母細胞的 IGF-1R 醣化作用 115 圖 20: GALNT2 修飾神經母細胞的IGF-1R活性，並調節IGF-1R 磷酸化及訊息傳遞 116 圖 21: IGF-1 抑制劑 (AG1024) 可抑制GALNT2-knockdown SK-N-DZ 細胞的惡性表現型 117 附錄 (碩博士班修業期間所發表之相關論文清冊) 118 | |
| dc.language.iso | zh-TW | |
| dc.subject | N-乙醯胺基半乳糖轉移? 2 | zh_TW |
| dc.subject | 3-乙醯葡萄糖胺轉移? 3 | zh_TW |
| dc.subject | β1 | zh_TW |
| dc.subject | 神經母細胞瘤 | zh_TW |
| dc.subject | O型醣基轉移? | zh_TW |
| dc.subject | 二聚體反應 | zh_TW |
| dc.subject | 類胰島素生長因子接受器 | zh_TW |
| dc.subject | 3-N-acetylglucosaminyltransferase-3 | en |
| dc.subject | O-glycosyltransferases | en |
| dc.subject | neuroblastoma | en |
| dc.subject | N-acetylgalactosaminyltransferase 2 | en |
| dc.subject | insulin-like growth factor-1 receptor | en |
| dc.subject | β1 | en |
| dc.subject | dimerization | en |
| dc.title | O 型醣基轉移酶在人類神經母細胞瘤所扮演的角色及其臨床重要性 | zh_TW |
| dc.title | The role of O-glycosyltransferases and their clinical significance in neuroblastoma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 103-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 楊偉勛,許文明,李明學,廖永豐,蔡有光 | |
| dc.subject.keyword | 神經母細胞瘤,O型醣基轉移?,β1,3-乙醯葡萄糖胺轉移? 3,N-乙醯胺基半乳糖轉移? 2,類胰島素生長因子接受器,二聚體反應, | zh_TW |
| dc.subject.keyword | β1,3-N-acetylglucosaminyltransferase-3,dimerization,insulin-like growth factor-1 receptor,N-acetylgalactosaminyltransferase 2,neuroblastoma,O-glycosyltransferases, | en |
| dc.relation.page | 120 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2015-04-13 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
| 顯示於系所單位： | 臨床醫學研究所 | |
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