系統識別號 U0026-2104201416591600
論文名稱(中文) 利用基因體及醣質體方法探索鑑定口腔癌腫瘤新型腫瘤標誌
論文名稱(英文) Genomic and glycomic identifications of novel tumor markers for oral cancer
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 陳怡婷
研究生(英文) Yi-Ting Chen
學號 S58971340
學位類別 博士
語文別 英文
論文頁數 145頁
口試委員 指導教授-張權發
中文關鍵字 口腔癌  轉移  AGR2蛋白  核心–岩藻醣化 
英文關鍵字 Oral cancer  Metastasis  Anterior gradient 2  Core-fucosylation 
中文摘要 目的:近年來,口腔癌為全球死亡率遞增的最常見的腫瘤之一,特別是在台灣;預防遠端器官的癌症轉移對於促進患者的生存率是可行的治療方法之一。另外,腫瘤細胞所表現特殊醣類結構曾被報導可以調節癌化進展,包括促進癌細胞的增殖、生長、粘附、行移及轉移等步驟。在此,我們試圖利用基因體及醣質體方法探索口腔癌癌化過程中新的治療標的治療標的或是腫瘤標記 。
實驗設計: 從人類口腔癌HSC-3以體外侵犯試驗分離並篩選出一高轉移性亞群細胞,接著利用基因表現微陣列技術進行比對尋找出基因圖譜中相異的醣基轉移酶基因或是其他基因,並藉由免疫組織化學染色法驗證所發現的基因的表現量。此外,純化細胞所表現的氮基醣類,並藉由基質輔助雷射脫附離子化-飛行時間質譜儀進行氮基醣類結構預測分析。
結果:我們利用侵犯試驗成功地從HSC-3細胞中,篩選分離出一具有相同遺傳物質但轉移性較高的亞群細胞(HSC-3-5細胞)。HSC-3-5細胞因細胞骨架重組伴隨導致形成上皮-間質轉化而有較高的轉移能力,同時,經由動物實驗證實HSC-3-5細胞更具腫瘤形成及轉移等能力。另外,進行HSC-3 及HSC-3-5細胞基因微陣列分析比對,鑑別指出促進癌化訊息調控的anterior gradient 2 (agr2)基因在HSC-3-5細胞中高度表現,藉由109 位口腔癌病人檢體驗證AGR2蛋白高度表達與癌症轉移有高靈敏度但低特異度的正向相關連性,AGR2蛋白可能是口腔癌轉移診斷的靈敏性生物標誌。同時,從微陣列基因表現分析在HSC-3-5細胞中,調控核心–岩藻醣化過程的fut8基因表現量較低,並從40位口腔癌病人檢體的免疫組織染色證實在轉移性腫瘤組織中核心-岩藻醣化現象較低。此外, AGR2蛋白高度表現的現象結合核心–岩藻醣化減量的現象,將可以改善對腫瘤轉移的陽性及陰性預測值。
英文摘要 Purpose: Oral cancer is one of the most commonly diagnosed tumors with increasing mortality worldwide, especially in Taiwan in recent years. Prevention of oral squamous carcinoma cancer metastasis to improve the overall survival has provided the rationale for biomarker development. In addition, specific glycans expressed in tumor cells have been identified as key mediators during the various progression steps of tumor including proliferation, growth, cell-cell adhesion, migration, and metastasis. Here, we are trying to explore novel therapeutic targets or tumor markers during oral cancer progression by genomics or glycomics approaches.
Experimental Design: A high metastatic sub-population was divided from human oral cancer HSC-3 by invasion assay in vitro. Gene expression microarray technology was performed to compare the different gene profiles, such as glycosyltransferases genes or others. Consequently, immunohistochemical staining was applied to verify expressions of identified genes. Further, N-glycans of cells were purified and subjected to Matrix-Assisted Laser Desorption Ionization –Time of Fight (MALDI-TOF) mass spectrometry analysis.
Results: We used Transwell invasion assay to successfully isolate a high-metastatic subpopulation, HSC-3-5 cells, which exhibited almost same genetic background with parental cells and higher metastatic capacities due to cytoskeletal rearrangement accompanied with epithelial mesenchymal transition. HSC-3-5 cells also showed tumorigenic and metastatic characteristics in vivo. In addition, anterior gradient 2 (agr2) gene, a pro-oncogenic signaling intermediate, was identified from gene expression profiles. Overexpression of AGR2 showed a high sensitivity, which positively correlated with metastasis in 109 oral cancer patients, and a poor specificity. AGR2 was likely a novel sensitive diagnostic marker for oral cancer metastasis. In the meanwhile, down-regulation of fut8 gene, which regulated the core-fucosylation process, was recognized in HSC-3-5 cells from the gene expression microarray and verified in metastatic tissues by 40 oral cancer patients of immunohistochemical staining. In addition, the positive and negative prediction values of metastasis could be improved through combination with decreased core-fucosylation and overexpression of AGR2.
Conclusions: AGR2 was suggested to be a novel sensitive biomarker for metastatic oral cancer. And combined core-fucosylation with AGR2 promoted the positive and negative predictive value of metastasis.
論文目次 中文摘要 I
Abstract III
誌謝 V
Index of Contents VI
Index of Table Information IX
Index of Figure Information X
Index of Supplemental Information XII
Contents 1
1. Introduction 1
1.1. Oral cancer 1
1.2. Oral cancer tumor markers 1
1.3. Tumor metastasis 2
1.4. Human Anterior Gradient 2 (AGR2) and AGR2 biological functions 4
1.5. Glycosylation and cancers 5
1.6. Fucosyltransferase 8 (FUT8) and core-fucosylation in cancer 7
2. Specific purpose and experimental flowchart 9
2.1. Specific purpose 9
2.2. Experimental flowchart 9
3. Materials and methods 12
3.1. Cell lines and tissue culture 12
3.2. Transwell Matrigel invasion assay 12
3.3. Invasion selection assay 13
3.4. Short tandem repeats (STR)- polymerase chain reaction (PCR) analysis 14
3.5. Wound healing assay 15
3.6. Real-time wound healing assay and signal cell tracking 15
3.7. Confocal microscopic analysis 16
3.8. Protein extraction and Western blot 16
3.9. In vivo spontaneous metastasis assay with heterotopic subcutaneous transplantation 17
3.10. Nested polymerase chain reaction (PCR) assay 18
3.11. In vivo experimental metastasis assay with intravenous transplantation 18
3.12. In vitro adhesion assay 19
3.13. MTT assay 19
3.14. Soft agar colony formation assay 20
3.15. In vivo spontaneous metastasis assay with orthotopic tongue transplantation 20
3.16. In vitro and in vivo gene expression microarray analysis 21
3.17. AGR2 siRNA transfection 21
3.18. Immunostaining analysis 22
3.19. Immunohistochemistry (IHC) analysis 23
3.20. Human oral cancer tissue array 24
3.21. N-glycan purification 24
3.22. N-glycans permethylation for Matrix-Assisted Laser Desorption Ionization –Time of Fight (MALDI-TOF) mass spectrometry analysis 26
3.23. Mass data evaluation for N-glycan prediction 27
3.24. RNA extraction and real-time quantitative polymerase chain reaction (PCR) assay 27
3.25. Cell cycle analysis by flow cytometry 29
3.26. Statistical analysis 29
4. Results 30
4.1. Highly metastatic HSC-3-5 cells capable of mesenchymal transformation were isolated 30
4.2. HSC-3-5 cells exhibited enhanced metastatic abilities and increased tumorigenesis in vitro and in vivo 31
4.3. Comparison of gene expression profiles between HSC-3 and HSC-3-5 cells via microarray analysis 33
4.4. AGR2 was involved in the regulation of cell migration 33
4.5. AGR2 protein expression patterns in xenografts, and tissue arrays 34
4.6. Overexpression of AGR2 was correlated with metastatic HNSCCs 35
4.7. Glycosyltransferase gene expression of HSC-3 and HSC-3-5 cells (microarray analysis) 36
4.8. N-glycan profiles of HSC-3 and HSC-3-5 cells (MALDI-TOF analysis) 37
4.9. Decreased core-fucosylation in cells and clinical tissues 38
4.10. Decreased core-fucosylation increased the positive prediction value of AGR2 with metastatic oral cancer 39
5. Discussion 41
6. Reference 48
Table information 56
Figure information 63
Supplementary Information 83
Appendices 144
1. Publications 144
2. Autobiography 145
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