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研究生:郭桓銜
研究生(外文):Huan-Hsien Kuo
論文名稱:SSEA-3,SSEA-4, Globo H與其合成相關的醣基轉移酶在人類胚胎幹細胞分化過程與在肝細胞癌中的表現
論文名稱(外文):The expression of SSEA-3, SSEA-4, Globo H and their biosynthetic glycosyltransferases during the differentiation of human embryonic stem cells and in hepatocellular carcinoma
指導教授:陳鈴津
指導教授(外文):Alice L. Yu
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:106
語文別:英文
論文頁數:72
中文關鍵詞:SSEA-3SSEA-4Globo H醣基轉移酶肝癌
外文關鍵詞:SSEA-3SSEA-4Globo HglycosyltransferaseHCC
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本論文的研究內容分成兩部份。第一部份是研究在人類胚胎幹細胞分化成不同譜系的過程中鞘醣脂以及與其合成相關的醣基轉移酶的表現。第二部份是研究SSEA-3,SSEA-4 與Globo H 及其合成相對應的醣基轉移酶在肝細胞癌中的表現。
鞘醣脂普遍存在於動物細胞的細胞膜上,能參與細胞的附著與訊息傳導並可作為特定細胞種類的標誌。在此研究中藉由基質輔助雷射脫附離子化-飛行時間質譜儀(Matrix-assisted laser desorption ionization-time of flight mass spectrometry, MALDI-TOF MS)的分析建立了人類胚胎幹細胞以及其分化所得到的類胚胎體(embryoid body),神經前驅細胞(neural progenitor cell)及限定性內胚層(definitive endoderm)的鞘醣脂(glycosphingolipid)的表現圖譜。在這研究中從人類胚胎幹細胞的鞘醣脂中鑑識出幹細胞標記階段特異性胚胎抗原-3(stage-specific embryonic antigen-3, SSEA-3)與階段特異性胚胎抗原-4(SSEA-4)以及其他數種以往未被報告有表現於胚胎幹細胞中的紅細胞醣苷(globoside)與乳糖系列的鞘醣脂(lacto-series GSL)。在未分化的胚胎幹細胞中的鞘醣脂的表現圖譜與已分化的細胞中有顯著的不同,而這現象也伴隨著數個重要的醣基轉移酶與有著不同的表現量。值得注意的是在分化的內胚層細胞仍有中Globo H表現,參與紅細胞醣苷系列的鞘醣脂合成的部分醣基轉移酶如B3GALT5, FUT1與FUT2雖然表現量相對於未分化的胚胎幹細胞表現量減少但仍比在神經前驅細胞高。
癌細胞可能來自去分化(dedifferentiation)的成熟細胞或成熟過程中受到抑制幹細胞。之前的研究發現能分化成肝臟的內胚層細胞中仍能偵測到SSEA-4 與Globo H。此研究中針對岩藻醣轉移酶-1 (FUT1),岩藻醣轉移酶-2(FUT2), b-1,3半乳糖轉移酶5(B3GALT5)及a-2,3唾液酸轉移酶2(ST3GAL2)使用即時聚合酶鏈鎖反應偵測這些基因在肝癌檢體中的表現。肝癌檢體中有較高FUT1或B3GALT5表現的病人有著明顯較差的癒後。使用Kaplan-Meier法分析,有高表現FUT1或B3GALT5的病人其無復發存活時間(relapse-free survival)顯著較短(P=0.023與0.010),高表現B3GALT5的病人其總存活時間(overall survival)也顯著較差(P=0.012)。將FUT1與B3GALT5合併成單一因子,同時高表現這兩個基因的病人有顯著較為短的無復發存活時間與總存活時間(P<0.001)。進而使用Cox多變量風險比例分析,結果顯示同時高表現FUT1與B3GALT5是除了臨床病理參數外,一種相對簡單能預測肝細胞癌病患在手術切除肝癌腫瘤後無復發存活與總存活的獨立因子。此外在本研究中使用免疫化學染色及質譜分析證明Globo H, SSEA-3與SSEA-4這些醣抗原在肝癌組織中有表現但是在正常肝組織則無,以及使用醣晶片分析血清中自發性辨識Globo H, SSEA-3 與SSEA-4 的抗體,結果顯示肝癌病患的這些自發抗體明顯的較無疾病的正常人多。
This dissertation is divided into two parts. The part one is the study of the expression of glycosphingolipids and their biosynthetic glycosyltransferases during human embryonic stem cell differentiation. The second part is the study of the expression of SSEA-3, SSEA-4 Globo H and their corresponding synthetic glycosyltransferase in HCC.
Glycosphingolipids (GSLs) are ubiquitous components of mammalian cell membranes that are involved in cell adhesion and signal transduction and possibly be used as cell type-specific markers.In this study, the GSL profiles of human embryonic stem cells (hESCs) and their differentiated embryoid body (EB) outgrowth, neural progenitors, and definitive endodermal cells were analyzed by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). The well-known hESC marker, SSEA-3, SSEA-4 and several globosides and lacto-series GSLs were identified in hESC. The GSLs profiling of hESC was dramatically different from those in the differentiated cells. The changes of GSL profiling were accompanied by the alterations in the expression of glycosyltransferases. Globo H was found in definitive endodermal cells. The glycosyltransferases involved in the biosynthesis of globo-series GSLs and lacto-series GSLs, such as FUT1, FUT2 and B3GALT5 were downregulated in definitive endodermal cells, but their expression levels were higher than those in the neural progenitor cells.
Cancer may arise from dedifferentiation of mature cells or maturation-arrested stem cells. Project 1 showed that definitive endoderm from which liver was derived, expressed Globo H, SSEA-3, and SSEA-4. In this study, we examined the expression of their biosynthetic enzymes, FUT1, FUT2, B3GALT5, and ST3GAL2, in 203 hepatocellular carcinoma (HCC) tissues by qRT-PCR. High expression of either FUT1 or B3GALT5 was significantly associated with poor outcome. Kaplan Meier survival analysis showed significantly shorter relapse-free survival (RFS) for those with high expression of either FUT1 or B3GALT5 (P = 0.023 and 0. 010, respectively) and shorter overall survival (OS) for those with high expression of B3GALT5 (P = 0.012). Combination of FUT1 and B3GALT5 revealed that high expression of both genes had poorer RFS and OS than the others (P < 0.001). Moreover, multivariable Cox regression analysis identified the combination of B3GALT5 and FUT1 as an independent predictor for RFS (HR: 1.985, 95% CI: 1.380-2.854, P < 0.001) and OS (HR: 1.927, 95% CI: 1.137-3.264, P = 0.015) in HCC. Our finding of combined high expression of FUT1 and B3TALT5 as an independent risk factor for postoperative recurrence and OS of HCC represents a simple and valuable addition to the existing clinicopathological parameters for the prognostication of HCC. In addition, the presence of Globo H, SSEA-3, and SSEA-4 in some HCC tissues and their absence in normal liver was established by immunohistochemistry staining and mass spectrometric analysis. The anti-SSEA3, SSEA4, and Globo H autoantibodies were significantly higher in HCC patient serum than those in the healthy individuals.
Acknowledgements....I
Abstract in Chinese....II
Abstract....IV
List of figures....VI
List of table....VIII
Table of contents....IX

Chapter 1 Expression of glycosphingolipids and their biosynthetic glycosyltransferases during human embryonic stem cell differentiation
1.1 Introduction....1
1.1.1 Human embryonic stem cells....1
1.1.2 Glycosphingolipids....1
1.2 Objectives....2
1.3 Materials and methods....3
1.3.1 hESC culture....3
1.3.2 Differentiation of hESCs into embryoid body....3
1.3.3 Differentiation of hESCs into neural progenitor cells....4
1.3.4 Differentiation of hESCs into definitive endoderm....4
1.3.5 Purification of GSLs....5
1.3.6 Matrix-assisted laser desorption ionization-time of flight analysis of permethylated GSLs....5
1.3.7 Quantitative reverse-transcription real-time polymerase chain reaction....5
1.4 Results and Discussion....6
1.4.1 MALDI-MS analyses of GSL expression patterns....6
1.4.2 Alterations in the expression of glycosyltransferase during embryonic stem cell differentiation into embryoid body outgrowth....7
1.4.3 The kinetics of the glycosyltransferases during the curse of differentiation of hESCs....8
1.4.4 Alterations of the expression of glycosyltransferase during differentiation of hESC into neural progenitor cells or definitive endoderm....8

Chapter 2 Chapter 2 Expression of SSEA-3, SSEA-4, Globo H and their biosynthetic glycosyltransferases in HCC
2.1 Introduction....10
2.1.1 Hepatocellular carcinoma (HCC)....10
2.1.1.1 Incidence and mortality of liver cancer....10
2.1.1.2 Epidemiology of HCC....11
2.1.1.3 Treatments for HCC....13
2.1.1.4 Prognosis of HCC....14
2.1.2 Glycoconjugates in mammalian cells....15
2.1.2.1 Glycosylation alterations in cancer....15
2.1.2.2 Aberrant glycosylation in HCC....15
2.1.2.3 Globo H and stage-specific embryonic antigen 3, 4....16
2.2 Objectives of the study....17
2.3 Materials and Methods....18
2.3.1 Quantitative reverse-transcription real-time polymerase chain reaction....18
2.3.2 Clinical specimens....18
2.3.3 Immunohistochemistry....19
2.3.4 Matrix-assisted laser desorption ionization-time of flight analysis of permethylated GSLs....20
2.3.5 Statistical analysis....21
2.3.6 Glycan microarray....21
2.4 Result....22
2.4.1 The RNA Expression levels of FUT1, FUT2, B3GALT5, and ST3GAL2 in HCC tissues....22
2.4.2 Correlation of clinicopathological parameters with the expression levels of FUT1, FUT2, B3GALT5, and ST3GAL2....23
2.4.3 High expression levels of FUT1 and B3GALT5 correlate with poor clinical outcome....24
2.4.4 High expression of FUT1 and B3GALT5 combined is an independent prognostic factor for HCC relapse and overall survival....25
2.4.5 Determination of the expression of Globo H, SSEA-3, and SSEA-4 in HCC and normal liver tissues....26
2.4.6 Comparison of the levels of serum anti-Globo H, SSEA-3 and SSEA-4 antibodies in HCC patients and healthy individuals....28
2.5 Discussion....29
3 Reference....33
4 Appendix....72
List of publication during Ph.D. student....72
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