臺灣博碩士論文加值系統

神經母細胞瘤（NB）是兒童期常見的惡性實體瘤，起源於神經母細胞的異常分化，主要影響交感神經節和腎上腺髓質。它約佔兒童癌症相關死亡的15%。
細胞表面的異常醣基化為癌細胞的顯著特徵之一，與惡性細胞轉化有關。這種非典型醣基化可能是由於生物合成酶的異常所造成，例如糖基轉移酶和核苷酸糖轉運蛋白。溶質載體家族35成員A2(SLC35A2)，為UDP-半乳糖轉運蛋白(UGT)，會將UDP-半乳糖轉運至高基氏體囊泡中參與醣基化。SLC35A2突變與先天性醣基化障礙疾病相關，但其在神經母細胞瘤中的作用仍不清楚。
在本研究中，我們透過臨床病理、生物學因素及免疫組織化學確認SLC35A2和MYCN在神經母細胞瘤中的臨床相關性。首先我們使用定量實時PCR分析了14種人類NB細胞系中SLC35A2的表現量。隨後，我們敲落或過表現SLC35A2基因以研究其對GI-ME-N、SKN-BE和SH-SY5Y細胞系表型的影響。研究結果表明，SLC35A2過表現顯著降低GI-ME-N的細胞活力，而在SKN-BE及SH-SY5Y細胞中抑制SLC35A2表現都顯著增加細胞活力。為了評估醣基化變化，我們使用了識別GlcNAc的LEL和STL等凝集素，結果顯示與對照組相比，SKN-BE細胞中的SLC35A2敲落導致GlcNAcylation增加。
此外，本研究還探討了SLC35A2在神經母細胞瘤中自噬作用和細胞凋亡的潛在參與。由於細胞自噬及細胞凋亡失調在多種疾病包括癌症有關。利用細胞凋亡測定顯示，與對照組相比，在葡萄糖剝奪條件下，SLC35A2敲落的SKN-BE細胞較不易死亡，而在穿透式電子顯微鏡及西方墨點法結果顯示，SLC35A2敲落會促進SKN-BE細胞自噬。總之，本研究強調了SLC35A2在調節神經母細胞瘤中醣蛋白改變和葡萄糖代謝中的潛在作用，並表明自噬的參與。然而，還需要進一步的研究來闡明SLC35A2和自噬作用在神經母細胞瘤發病機制中的潛在機制和影響。

Neuroblastoma (NB) is a common malignant solid tumor in childhood that originates from abnormal differentiation of neuroblasts, primarily affecting the sympathetic ganglia and adrenal medulla. It accounts for approximately 15% of childhood cancer-related deaths. Aberrant glycosylation on the cell surface is one of the prominent characteristics of cancer cells and is associated with malignant cell transformation. This atypical glycosylation may be caused by abnormalities in biosynthetic enzymes such as glycosyltransferases and nucleotide sugar transporters. Solute carrier family 35 member A2 (SLC35A2), also known as UDP-galactose transporter (UGT), transports UDP-galactose into the Golgi apparatus vesicles for glycosylation. Mutations in SLC35A2 are associated with congenital disorders of glycosylation, but its role in neuroblastoma remains unclear. In this study, we investigated the clinical relevance of SLC35A2 and MYCN in neuroblastoma through clinical pathology, biological factors, and immunohistochemistry. Firstly, we analyzed the expression levels of SLC35A2 in 14 human neuroblastoma cell lines using quantitative real-time PCR. Subsequently, we knocked down or overexpressed the SLC35A2 gene to study its effects on the phenotype of GI-ME-N, SKN-BE, and SH-SY5Y cell lines. The results showed that overexpression of SLC35A2 significantly reduced cell viability in GI-ME-N cells, while inhibiting SLC35A2 expression in SKN-BE and SH-SY5Y cells significantly increased cell viability. To evaluate glycosylation changes, we used lectins such as LEL and STL that recognize GlcNAc residues, and the results showed that SLC35A2 knockdown in SKN-BE cells led to increased GlcNAcylation compared to the control group. Furthermore, this study also investigated the potential involvement of SLC35A2 in autophagy and apoptosis in neuroblastoma. Dysregulation of autophagy and apoptosis is associated with various diseases, including cancer. Apoptosis assays demonstrated that SKN-BE cells with SLC35A2 knockdown were less prone to cell death under glucose deprivation conditions, and transmission electron microscopy and Western blotting results indicated that SLC35A2 knockdown promoted autophagy in SKN-BE cells. In conclusion, this study highlights the potential role of SLC35A2 in regulating glycoprotein alterations and glucose metabolism in neuroblastoma and suggests the involvement of autophagy. However, further research is needed to elucidate the potential mechanisms and impacts of SLC35A2 and autophagy in the pathogenesis of neuroblastoma.

誌謝 i
摘要 ii
Abstract iii
縮寫表(Abbreviation) v
目錄(Contents) vii
圖目錄（List of Figures） x
表目錄（List of Tables） xi
第一章 緒論（Introduction） 1
1.1神經母細胞瘤(Neuroblastoma) 1
1.1.1神經母細胞瘤的流行病學 1
1.1.2神經母細胞瘤的致病原因與病理成因 2
1.1.4神經母細胞瘤的病理分類與臨床分期 5
1.1.5神經母細胞瘤的治療 9
1.2醣基化(Glycosylation) 12
1.2.1異常的醣基化 12
1.2.2糖基轉移酶(Glycosyltransferases) 14
1.2.3核苷酸糖轉運蛋白(Nucleotide Sugar Transporters, NST) 15
1.3自體吞噬(Autophagy) 17
1.3.1自噬作用與細胞凋亡(Autophagy and Apoptosis) 17
1.3.2自噬作用與癌症(Autophagy and Cancer) 20
第二章 研究目的（Aim） 22
2.1探討SLC35A2在神經母細胞瘤中的角色 22
2.2探討SLC35A2和自噬作用在神經母細胞瘤發病機制中的潛在機制和影響 22
第三章 研究材料與方法（Materials & Methods） 23
3.1實驗材料（Materials） 23
3.1.1抗體（Antibody） 23
3.1.2引子（Primers） 23
3.1.3 RNA interference（shRNA） 23
3.1.4藥品、試劑及其他（Drugs、Reagents and Others） 24
3.1.5儀器設備（Instruments and Equipment） 27
3.2病患資料與檢體收集（Patients and tissue samples） 28
3.3組織石蠟包埋與切片（Paraffin embedding & Paraffin section） 28
3.4免疫組織化學染色法（Immunohistochemistry staining; IHC） 29
3.5蘇木精-伊紅染色（Hematoxylin & Eosin stain） 30
3.6免疫螢光染色（Immunofluorescence staining; IF） 31
3.7細胞株及細胞培養（Cell lines & Cell culture） 32
3.8控制細胞SLC35A2表現 32
3.9細胞蛋白質萃取、定量及配製樣本（Cell Protein extraction & Bradford protein assay & Prepare protein sample） 32
3.10西方墨點法（Western blot） 33
3.11 RNA萃取與反轉錄-聚合酶連鎖反應（RNA Extraction & Reverse Transcription Polymerase Chain Reaction, RT-PCR） 35
3.12定量反轉錄-聚合酶連鎖反應（Real-time Polymerase Chain Reaction; Quantitative RT-PCR, RT-qPCR） 36
3.13細胞存活率分析（Cell viability assay; MTT assay） 36
3.14流式細胞儀（Flow cytometry） 36
3.15 穿透式電子顯微鏡細胞樣本包埋（Transmission Electron microscope cell sample embedding） 36
3.16統計分析（Statistical analysis） 37
第四章 結果（Results） 39
4.1 SLC35A2在神經母細胞瘤病患中的表現及其與臨床病理和生物性因子的關聯性 39
4.2 SLC35A2的表現與存活率之分析 39
4.3 SLC35A2過表達增加在NB細胞的高基氏體中大量表現 40
4.4 Knockdown SLC35A2會增加神經母細胞瘤的GlcNAcylation 41
4.5 Knockdown SLC35A2會增強神經母細胞瘤的活性及形成群落能力 41
4.6在無葡萄糖與無血清環境中，knockdown SLC35A2的神經母細胞瘤細 胞較不易死亡 42
4.7 Knockdown SLC35A2會導致在神經母細胞瘤中的自噬作用增強 42
第五章 結論（Conclusion） 44
第六章 討論（Discussion） 46
第七章 圖表（Tables & Figures） 48
第八章 參考文獻（References） 62

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