系統識別號 U0026-0512202017205200
論文名稱(中文) 探討TIAM2過度表現所引發癌化的機制
論文名稱(英文) Study of TIAM2 overexpression induced tumorigenesis
校院名稱 成功大學
系所名稱(中) 生物科技與產業科學系
系所名稱(英) Department of Biotechnology and Bioindustry Sciences
學年度 109
學期 1
出版年 109
研究生(中文) 詹雅玲
研究生(英文) Ya-Ling Chan
學號 Z28011043
學位類別 博士
語文別 英文
論文頁數 65頁
口試委員 指導教授-孫孝芳
中文關鍵字 人類 T 細胞淋巴癌侵略和轉移基因 2  氧化偶氮甲烷  慢性發炎  血清素  大腸直腸癌 
英文關鍵字 T-cell lymphoma invasion and metastasis 2  azoxymethane  chronic inflammation  serotonin  colorectal cancer 
中文摘要 人類T細胞淋巴癌侵略和轉移基因2 (T-cell lymphoma invasion and metastasis 2),短型RNA異構體;簡稱TIAM2S,它是人類腦部特異性表現的蛋白,在肝癌病人檢體中可以檢測到TIAM2S的異位性表現,然而,TIAM2S的致癌作用和分子機制尚不清楚。本研究的目的在探討TIAM2S在自發產生的腫瘤和致癌物誘導的腫瘤發生中所扮演的角色,因此,我們建立表現人類TIAM2S過度表現的轉置基因 (TIAM2S-TG) 小鼠,並且詳細描述這些基因轉殖鼠的基因型和表型特徵。另外,我們透過致癌物-氧化偶氮甲烷 (azoxymethane,簡稱AOM) 誘導的大腸癌模型來檢測TIAM2S-TG小鼠的腫瘤易感性。實驗結果發現TIAM2S-TG小鼠會誘導慢性發炎並導致全身多種器官出現高度淋巴細胞浸潤的產生,此外,AOM誘導的大腸癌模型中,我們發現TIAM2S-TG小鼠形成大腸直腸癌的年齡比野生型小鼠更早。經由免疫細胞的檢查和細胞因子/趨化因子的表達譜分析,我們發現血清素會影響免疫功能造成發炎性腸道疾病,導致TIAM2S-TG小鼠在第三淋巴器官中IL-23+/IL-17+/CD8+T淋巴細胞表現異常。總而言之,我們的研究證實TIAM2S過度表達會誘導慢性炎症並增加腸細胞對環境侵襲的敏感性,導致發展成大腸直腸癌。
英文摘要 Human T-cell lymphoma invasion and metastasis 2 (a human brain-specific protein), named as TIAM2 short form (TIAM2S), encodes short mRNA isoforms. Our previous studies have shown that the TIAM2S in liver cells promotes liver cancer tumorigenesis. However, the mechanism underlying its oncogenic effect remains unclear. This study aims to investigate the role of TIAM2S in spontaneous and carcinogen-induced tumorigenesis. We established TIAM2S-overexpressing transgenic (TG) mouse lines and characterized the genotypes and phenotypes in great details. In addition, we applied an azoxymethane (AOM)-induced colon cancer model to examine tumor susceptibility in these TIAM2S-TG mice. We found that the TIAM2S-expressing murine model developed chronic inflammation and had high incidence of lymphocytic infiltration in various organs. Furthermore, AOM-induced colon tumor developed at a younger age in the TIAM2S-TG mice than in the wild type (WT) mice. We examined immune cells and cytokine/chemokine profiles and found that serotonin-mediated inflammatory bowel disease (IBD), particularly IL-23+/IL-17+/CD8+T lymphocytes were characterized in the tertiary lymphoid organs (TLOs) in the TIAM2S-TG mice. Overall, this study shows that TIAM2S mediates chronic inflammation and increases the susceptibility of colon cells to environmental stresses and leads to the development of colorectal cancer (CRC).
論文目次 Chinese Abstract (中文摘要) I
Abstract II
Acknowledgements V
Table of Contents VI
Contents of Tables IX
Contents of Figures X
Contents of Appendices XI
Abbreviation List XII
Chapter 1 Research Background 1
1-1 Cancer progression 1
1-2 Tumor cell growth, invasion and migration 1
1-3 Tumor microenvironment 2
1-4 Inflammation 3
1-5 serotonin-mediated inflammation 5
1-6 Colitis-associated colon cancer 6
1-7 TIAM family 7
1-8 TIAM1 7
1-9 TIAM2 8
1-10 Possible physiological functions of TIAM2 in humans 9
1-11 The role of TIAM2 in tumorigenesis 9
1-12 Research objectives 10
Chapter 2 Materials and Methods 12
2-1 Establishing the TIAM2 overexpression mouse model 12
2-2 Southern blot hybridization 12
2-3 Genotyping 13
2-4 Mice 14
2-5 TIAM2S-TG mice treated with AOM 15
2-6 RT-PCR analysis 15
2-7 Haematoxylin and eosin staining 15
2-8 Immunohistochemistry 16
2-9 Cell lines 17
2-10 In vivo FMT analysis 17
2-11 Western blot analysis 18
2-12 Protein and antibody preparation 18
2-13 Semi-quantification of protein expression in human colorectal cancer cell lines 19
2-14 Body weight and survival assessments 19
2-15 Analysis of cytokine and chemokine secretion from mouse serum and colon tissue 20
2-16 Analysis of T lymphocytes using flow cytometry 20
2-17 Quantification of IHC staining 21
2-18 Statistical analysis 21
Chapter 3 Results 22
3-1 Increased lymphocytic infiltration in various organs of TIAM2S-TG mice 22
3-2 Development of a colon tumor model in TIAM2S-TG mice 23
3-3 TIAM2S expression alters serotonin-induced immune response in TG mice 24
3-4 TIAM2S induces inflammation and progresses colonic tumorigenesis 28
Chapter 4 Discussion 31
References 37
Tables 47
Figures 50
Appendices 62
Related Paper Publications 65
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