進階搜尋


下載電子全文  
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
共同指導教授-曾大千
口試委員-王憶卿
口試委員-蔡少正
口試委員-戴明泓
口試委員-陳琮明
口試委員-劉柯俊
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 
學科別分類
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
參考文獻 Ahern, G.P. 5-HT and the immune system. Current Opinion in Pharmacology 11, 29-33, 2011.

Alfarouk, K.O., Muddathir, A.K. and Shayoub, M.E. Tumor acidity as evolutionary spite. Cancers 3, 408-414, 2011.

Alitalo, A. and Detmar, M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31, 4499-4508, 2012.

Amieva, M. and Peek, R.M. Jr. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology 150, 64-78, 2016.

Antonioli, L., Fornai, M., Pellegrini, C., Masi, S., Puxeddu, I. and Blandizzi, C. Ectopic lymphoid organs and immune-mediated diseases: molecular basis for pharmacological approaches. Trends in Molecular Medicine 26, 1021-1033, 2020.

Avkin, S., Goldsmith, M., Velasco-Miguel, S., Geacintov, N., Friedberg, E.C. and Livneh, Z. Quantitative analysis of translesion DNA synthesis across a benzo[a] pyrene-guanine adduct in mammalian cells: The role of DNA polymerase kappa. Journal of Biological Chemistry 279, 53298-53305, 2004.

Balkwill, F. and Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539-545, 2001.

Bhattacharyya, S., Dudeja, P.K. and Tobacman, J.K. ROS, Hsp27, and IKKbeta mediate dextran sodium sulfate (DSS) activation of IkappaBa, NFkappaB, and IL-8. Inflammatory Bowel Diseases 15, 673-683, 2009.

Buckley, C.D., Barone, F., Nayar, S., Benezech, C. and Caamano, J. Stromal cells in chronic inflammation and tertiary lymphoid organ formation. Annual Review of Immunology 33, 715-745, 2015.

Cardiff, R.D., Miller, C.H. and Munn, R.J. Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harbor Protocols 6, 655-658, 2014.

Carlsen, H.S., Baekkevold, E.S., Johansen, F.E., Haraldsen, G. and Brandtzaeg, P. B Cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue. Gut 51, 364-371, 2002.

Chambers, A.F., Groom, A.C. and MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites. Nature Reviews Cancer 2, 563-572, 2002.

Chen, J.S., Su, I.J., Leu, Y.W., Young, K.C. and Sun, H.S. Expression of T-cell lymphoma invasion and metastasis 2 (TIAM2) promotes proliferation and invasion of liver cancer. International Journal of Cancer 130, 1302-1313, 2012.

Chen, S.M.Y., Krinsky, A.L., Woolaver, R.A., Wang, X., Chen, Z. and Wang, J.H. Tumor immune microenvironment in head and neck cancers. Molecular Carcinogenesis 59, 766-774, 2020.

Chiu, C.Y., Leng, S., Martin, K.A., Kim, E., Gorman, S. and Duhl, D.M. Cloning and characterization of T-cell lymphoma invasion and metastasis 2 (TIAM2), a novel guanine nucleotide exchange factor related to TIAM1. Genomics 61, 66-73, 1991.

Chu, C.H., Chen, J.S., Chuang, P.C., Su, C.H., Chan, Y.L., Yang, Y.J., Chiang, Y.T., Su, Y.Y., Gean, P.W. and Sun, H.S. TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior. Federation of American Societies for Experimental Biology Journal 34, 3267-3288, 2020.

Cohen, J. The immunopathogenesis of sepsis. Nature 420, 885-891, 2002.

Corkum, C.P., Ings, D.P., Burgess, C., Karwowska, S., Kroll, W. and Michalak, T.I. Immune cell subsets and their gene expression profiles from human PBMC isolated by Vacutainer Cell Preparation Tube (CPT) and standard density gradient. BMC Immunology 16, 48, 2015.

Coussens, L.M. and Werb, Z. Inflammation and cancer. Nature 420, 860-867, 2002.

Crosbie, E.J., Einstein, M.H., Franceschi, S. and Kitchener, H.C. Human papilloma virus and cervical cancer. Lancet 382, 889-899, 2013.

Davis, J.M., Alderson, N.L. and Welsh, R.S. Serotonin and central nervous system fatigue: nutritional considerations. American Journal of Clinical Nutrition 72, 573-578, 2000.

Dentel, C., Palamiuc, L., Henriques, A., Lannes, B., Spreux-Varoquaux, O., Gutknecht, L., René, F., Echaniz-Laguna, A., Gonzalez de Aguilar, J.L., Lesch, K.P., Meininger, V., Loeffler, J.P. and Dupuis, L. Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity. Brain 136, 483-493, 2013.

Dfarhud, D., Malmir, M. and Khanahmadi, M. Happiness and health: the biological factors- systematic review article. Iranian Journal of Public Health 43, 1468-1477, 2014.

Ding, Y., Chen, B., Wang, S., Zhao, L., Chen, J.Z., Ding, Y.Q., Chen, L.H. and Luo, R.C. Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC patients. International Journal of Cancer 124, 653-658, 2009.

Du, F., Garg, A.V., Kosar, K., Majumder, S., Kugler, D.G., Mir, G.H., Maggio, M., Henkel, M., Lacy-Hulbert, A. and McGeachy, M.J. Inflammatory Th17 cells express integrin alphavbeta3 for pathogenic function. Cell Reports 16, 1339-1351, 2016.

Duvallet, E., Semerano, L., Assier, E., Falgarone, G. and Boissier, M.C. Interleukin-23: a key cytokine in inflammatory diseases. Annals of Medicine 43, 503-511, 2011.

Erickson, M.A. and Banks, W.A. Cytokine and chemokine responses in serum and brain after single and repeated injections of lipopolysaccharide: multiplex quantification with path analysis. Brain, Behavior, and Immunity 25, 1637-1648, 2011.

Etienne-Manneville, S. and Hall, A. Rho GTPases in cell biology. Nature 420, 629-635, 2002.

Fabre, J., Giustiniani, J., Garbar, C., Antonicelli, F., Merrouche, Y., Bensussan, A., Bagot, M. and Al-Dacak, R. Targeting the tumor microenvironment: the protumor effects of IL-17 related to cancer type. International Journal of Molecular Sciences 17, 1433, 2016.

Fleming, I.N., Batty, I.H., Prescott, A.R., Gray, A., Kular, G.S., Stewart, H. and Downes, C.P. Inositol phospholipids regulate the guanine-nucleotide-exchange factor Tiam1 by facilitating its binding to the plasma membrane and regulating GDP/GTP exchange on Rac1. Biochemical Journal 382, 857-865, 2004.

Fleming, I.N., Gray, A. and Downes, C.P. Regulation of the Rac1-specific exchange factor Tiam1 involves both phosphoinositide 3-kinase-dependent and -independent components. Biochemical Journal 351, 173-182, 2000.

Freeman, M.L., Mudd, J.C., Shive, C.L., Younes, S.A., Panigrahi, S., Sieg, S.F., Lee, S.A., Hunt, P.W., Calabrese, L.H., Gianella, S., Rodriguez, B. and Lederman, M.M. CD8 T-Cell Expansion and Inflammation Linked to CMV Coinfection in ART-treated HIV Infection. Clinical Infectious Diseases 62, 392-396, 2016.

Freire, M.O. and Van Dyke, T.E. Natural resolution of inflammation. Periodontology 2000 63, 149-164, 2013.

Fujiwara, N. and Kobayashi, K. Macrophages in inflammation. Current Drug Targets-Inflammation and Allergy 4, 281-286, 2005.

Garcia, J.M., Garcia, V., Pena, C., Dominguez, G., Silva, J., Diaz, R., Espinosa, P., Citores, M.J., Collado, M. and Bonilla, F. Extracellular plasma RNA from colon cancer patients is confined in a vesicle-like structure and is mRNA-enriched. RNA 14, 1424-1432, 2008.

Gershon, M.D. Serotonin: its role and receptors in enteric neurotransmission. Advances in Experimental Medicine and Biology 294, 221-230, 1991.

Graves, E.E., Maity, A. and Le, Q.T. The tumor microenvironment in non-small-cell lung cancer. Seminars in Radiation Oncology 20, 156-163, 2010.

Gremse, F., Doleschel, D., Zafarnia, S., Babler, A., Jahnen-Dechent, W., Lammers, T., Lederle, W. and Kiessling, F. Hybrid CT-FMT imaging and image analysis. Journal of Visualized Experiments 100, e52770, 2015.

Grivennikov, S.I., Greten, F.R. and Karin, M. Immunity, inflammation, and cancer. Cell 140, 883-899, 2010.

Guthrie, G.J., Charles, K.A., Roxburgh, C.S., Horgan, P.G., McMillan, D.C. and Clarke, S.J. The systemic inflammation-based neutrophil-lymphocyte ratio: experience in patients with cancer. Critical Reviews in Oncology Hematology 88, 218-230, 2013.

Habets, G.G., Scholtes, E.H., Zuydgeest, D., van der kammen, R.A., Stam, J.C., Berns, A. and Collard, J.G. Identification of an Invasion-Inducing Gene, Tiam-1, that encodes a protein with homology to Gdp-Gtp exchangers for Rho-like proteins. Cell 77, 537-549, 1994.

Hamada, Y., Murakami, I., Kato, E., Yamane, S., Fujino, H., Matsumoto, K., Tashima, K., Horie, S. and Murayama, T. Neurogenic contraction of mouse rectum via the cylooxygenase pathway: changes of PGE2-induced contraction with dextran sulfate sodium-induced colitis. Pharmacological Research 61, 48-57, 2010.

Hanahan, D. and Weinberg, R.A. The hallmarks of cancer. Cell 100, 57-70, 2000.

Hanahan, D. and Weinberg, R.A. Hallmarks of cancer: the next generation. Cell 144, 646-674, 2011.

Hartnett, L. and Egan, L.J. Inflammation, DNA methylation and colitis-associated cancer. Carcinogenesis 33, 723-731, 2012.

Hayashi, Y., Narumi, K., Tsuji, S., Tsubokawa, T., Nakaya, M., Wakayama, T., Zuka, M., Ohshima, T., Yamagishi, M. and Okada, T. Impact of adrenomedullin on dextran sulfate sodium-induced inflammatory colitis in mice: insights from in vitro and in vivo experimental studies. International Journal of Colorectal Disease 26, 1453-1462, 2011.

Heasman, S.J. and Ridley, A.J. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nature Reviews Molecular Cell Biology 9, 690-701, 2008.

Heng, H.H., Liu, G., Stevens, J.B., Bremer, S.W., Ye, K.J. and Ye, C.J. Genetic and epigenetic heterogeneity in cancer: the ultimate challenge for drug therapy. Current Drug Targets 11, 1304-1316, 2010.

Herr, N., Bode, C. and Duerschmied, D. The effects of serotonin in immune cells. Frontiers in Cardiovascular Medicine 4, 48, 2017.

Hiraoka, N., Ino, Y. and Yamazaki-Itoh, R. Tertiary lymphoid organs in cancer tissues. Frontiers in Immunology 7, 244, 2016.

Husson, H., Freedman, A.S., Cardoso, A.A., Schultze, J., Munoz, O., Strola, G., Kutok, J., Carideo, E.G., De Beaumont, R., Caligaris-Cappio, F. and Ghia, P. CXCL13 (BCA-1) is produced by follicular lymphoma cells: role in the accumulation of malignant B cells. British Journal of Haematology 119, 492-495, 2002.

Ikeda, S., Ushio-Fukai, M., Zuo, L., Tojo, T., Dikalov, S., Patrushev, N.A. and Alexander, R.W. Novel role of ARF6 in vascular endothelial growth factor-induced signaling and angiogenesis. Circulation Research 96, 467-475, 2005.

Iwakura, Y. and Ishigame, H. The IL-23/IL-17 axis in inflammation. Journal of Clinical Investigation 116, 1218-1222, 2006.

Jaffe, A.B. and Hall, A. Rho GTPases: biochemistry and biology. Annual Review of Cell and Developmental Biology 21, 247-269, 2005.

Jayasingam, S.D., Citartan, M., Thang, T.H., Mat Zin, A.A., Ang, K.C. and Ch'ng, E.S. Evaluating the polarization of tumor-associated macrophages into M1 and M2 phenotypes in human cancer tissue: technicalities and challenges in routine clinical practice. Frontiers in Oncology 9, 1512, 2020.

Joyce, J.A. and Pollard, J.W. Micro environmental regulation of metastasis. Nature Reviews Cancer 9, 239-252, 2009.

Kannen, V., Bader, M., Sakita, J.Y., Uyemura, S.A. and Squire, J.A. The dual role of serotonin in colorectal cancer. Trends in Endocrinology and Metabolism 31, 611-625, 2020.

Kawauchi, T., Chihama, K., Nabeshima, Y. and Hoshino, M. The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration. European Molecular Biology Organization Journal 22, 4190-4201, 2003.

Kema, I.P., de Vries, E.G. and Muskiet, F.A. Clinical chemistry of serotonin and metabolites. Journal of Chromatography B Biomedical Sciences and Applications 747, 33-48, 2000.

Khor, B., Gardet, A. and Xavier, R.J. Genetics and pathogenesis of inflammatory bowel disease. Nature 474, 307-317, 2011.

Kim, J.S. and Jordan, M.S. Diversity of IL-17-producing T lymphocytes. Cellular and Molecular Life Sciences 70, 2271-2290, 2013.

Kim, S.W., Roh, J. and Park, C.S. Immunohistochemistry for pathologists: protocols, pitfalls, and tips. Journal of Pathology and Translational Medicine 50, 411-418, 2016.

Konda, A. and Duffy, M.C. Surveillance of patients at increased risk of colon cancer: inflammatory bowel disease and other conditions. Gastroenterology Clinics of North America 37, 191-213, 2008.

Krzyszczyk, P., Schloss, R., Palmer, A. and Berthiaume, F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Frontiers in Physiology 9, 419, 2018.

Kundu, J.K. and Surh, Y.J. Emerging avenues linking inflammation and cancer. Free Radical Biology and Medicine 52, 2013-2037, 2012.

Lambert, J.M., Lambert, Q.T., Reuther, G.W., Malliri, A., Siderovski, D.P., Sondek, J., Collard, J.G. and Der, C.J. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biology 4, 621-625, 2002.

Lasry, A., Zinger, A. and Ben-Neriah, Y. Inflammatory networks underlying colorectal cancer. Nature Immunology 17, 230-240, 2016.

Libby, P. Inflammation in atherosclerosis. Nature 420, 868-874, 2002.

Lin, L., Hu, X., Zhang, H. and Hu, H. Tertiary lymphoid organs in cancer immunology: mechanisms and the new strategy for immunotherapy. Frontiers in Immunology 10, 1398, 2019.

Liotta, L.A. and Kohn, E.C. The microenvironment of the tumour-host interface. Nature 411, 375-379, 2001.

Lipsky, P.E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nature Immunology 2, 764-766, 2001.

Liu, Y., Zhang, Z., Wang, L., Li, J., Dong, L., Yue, W., Chen, J., Sun, X., Zhong, L. and Sun, D. TLR4 monoclonal antibody blockade suppresses dextran-sulfate-sodium-induced colitis in mice. Journal of Gastroenterology and Hepatology 25, 209-214, 2010.

Luzina, I.G., Todd, N.W., Nacu, N., Lockatell, V., Choi, J., Hummers, L.K. and Atamas, S.P. Regulation of pulmonary inflammation and fibrosis through expression of integrins alphaVbeta3 and alphaVbeta5 on pulmonary T lymphocytes. Arthritis and Rheumatism 60, 1530-1539, 2009.

Malinova, T.S., Dijkstra, C.D. and de Vries, H.E. Serotonin: a mediator of the gut–brain axis in multiple sclerosis. Multiple Sclerosis Journal 24, 1144-1150, 2018.

Maucort-Boulch, D., de Martel, C., Franceschi, S. and Plummer, M. Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide. International Journal of Cancer 142, 2471-2477, 2018.

Mawe, G.M. and Hoffman, J.M. Serotonin signalling in the gut-functions, dysfunctions and therapeutic targets. Nature Reviews Gastroenterology and Hepatology 10, 473-486, 2013.

Mertens, A.E., Roovers, R.C. and Collard, J.G. Regulation of Tiam1-Rac signalling. Federation of European Biochemical Societies Letters 546, 11-16, 2003.

Meunier, C., Cai, J., Fortin, A., Kwan, T., Marquis, J.F., Turbide, C., Van Der Kraak, L., Jothy, S., Beauchemin, N. and Gros, P. Characterization of a major colon cancer susceptibility locus (Ccs3) on mouse chromosome 3. Oncogene 29, 647-661, 2010.

Meyerhoff, J. and Dorsch, C.A., Decreased platelet serotonin levels in systemic lupus erythematosus. Arthritis and Rheumatism 24, 1495-1500, 1981.

Michiels, F., Habets, G.G., Stam, J.C., van der Kammen, R.A. and Collard, J.G. A role for rac in tiam1-induced membrane ruffling and invasion. Nature 375, 338-340, 1995.

Minard, M.E., Kim, L.S., Price, J.E. and Gallick, G.E. The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Research and Treatment 84, 21-32, 2004.

Muller, C.L., Anacker, A.M.J. and Veenstra-VanderWeele, J. The serotonin system in autism spectrum disorder: from biomarker to animal models. Neuroscience 321, 24-41, 2016.

Muller, W.A. Getting leukocytes to the site of inflammation. Veterinary Pathology 50, 7-22, 2013.

Nau, F. Jr., Miller, J., Saravia, J., Ahlert, T., Yu, B., and Happel, K.I., Cormier, S.A. and Nichols, C.D. Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model. American Journal of Physiology-Lung Cellular and Molecular Physiology 308, 191-198, 2015.

Neufert, C., Becker, C. and Neurath, M.F. An inducible mouse model of colon carcinogenesis for the analysis of sporadic and inflammation-driven tumor progression. Nature Protocols 2, 1998-2004, 2007.

Neurath, M.F. Cytokines in inflammatory bowel disease. Nature Reviews Immunology 14, 329-342, 2014.

Nishimura, T., Yamaguchi, T., Kato, K., Yoshizawa, M., Nabeshima, Y., Ohno, S., Hoshino, M. and Kaibuchi, K. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nature Cell Biology 7, 270-277, 2005.

Ohsugi, T. and Kumasaka, T. Low CD4/CD8 T-cell ratio associated with inflammatory arthropathy in human T-cell leukemia virus type I Tax transgenic mice. Public Library of Science One 6, e18518, 2011.

Peddareddigari, V.G., Wang, D. and Dubois, R.N. The tumor microenvironment in colorectal carcinogenesis. Cancer Microenviron 3, 149-166, 2010.

Pitt, J.M., Marabelle, A., Eggermont, A., Soria, J.C., Kroemer, G. and Zitvogel, L. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Annals of Oncology 27, 1482-1492, 2016.

Proctor, M.C., Cho, K.J. and Greenfield, L.J. Development and evaluation of Investigational vena caval filters: The complementary roles of in vitro and in vivo studies. Journal of Surgical Research 110, 241-254, 2003.

Qi, Y., Huang, B., Yu, L.L., Wang, Q., Lan, G.P. and Zhang, Q.H. Prognostic value of Tiam1 and Rac1 overexpression in nasopharyngeal carcinoma. Orl-Journal for Oto-Rhino-Laryngology and Its Related Specialties 71, 163-171, 2009.

Ragab, O., Khairy, N., Taha, R. and Iskander, M. Serum serotonin in rheumatoid arthritis patients: Relation to rheumatoid factor positivity, clinical manifestations and fibromyalgia. Egyptian Rheumatologist 40, 149-153, 2018.

Ray, K. Deciphering the role of CD8+ T cells in IBD: from single-cell analysis to biomarkers. Nature Reviews Gastroenterology and Hepatology 17, 595, 2020.

Ridley, A.J. Rho GTPases and cell migration. Journal of Cell Science 114, 2713-2722, 2001.

Robbins, P.D. and Morelli, A.E. Regulation of immune responses by extracellular vesicles. Nature Reviews Immunology 14, 195-208, 2014.

Rohatgi, R., Ma, L., Miki, H., Lopez, M., Kirchhausen, T., Takenawa, T. and Kirschner, M.W. The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly. Cell 97, 221-231, 1999.

Rosenberg, D.W., Giardina, C. and Tanaka, T. Mouse models for the study of colon carcinogenesis. Carcinogenesis 30, 183-196, 2009.

Rossman, K.L., Der, C.J. and Sondek, J. GEF means go: Turning on Rho GTPases with guanine nucleotide-exchange factors. Nature Reviews Molecular Cell Biology 6, 167-180, 2005.

Ruifrok, A.C. and Johnston, D.A. Quantification of histochemical staining by color deconvolution. Analytical and Quantitative Cytology and Histology 23, 291-299, 2001.

Ryozawa, S., Watanabe, H., Abe, M., Ajioka, Y., Nishikura, K. and Okita, K. Macroscopic and stereomicroscopic diagnosis of superficial flat-type early carcinomas of the gallbladder. Journal of Gastroenterology 32, 635-642, 1997.

Saleh, M. and Trinchieri, G. Innate immune mechanisms of colitis and colitis-associated colorectal cancer. Nature Reviews Immunology 11, 9-20, 2011.

Schlienger, R.G. and Meier, C.R. Effect of selective serotonin reuptake inhibitors on platelet activation: can they prevent acute myocardial infarction? American Journal of Cardiovascular Drugs 3, 149-162, 2003.

Selders, G.S., Fetz, A.E., Radic, M.Z. and Bowlin, G.L. An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regenerative Biomaterials 4, 55-68, 2017.

Serrano-Villar, S., Sainz, T., Lee, S.A., Hunt, P.W., Sinclair, E., Shacklett, B.L., Ferre, A.L., Hayes, T.L., Somsouk, M., Hsue, P.Y., Van Natta, M.L., Meinert, C.L., Lederman, M.M., Hatano, H., Jain, V., Huang, Y., Hecht, F.M., Martin, J.N., McCune, J.M., Moreno, S. and Deeks, S.G. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. Public Library of Science Pathogens 10, e1004078, 2014.

Shajib, M.S. and Khan, W.I. The role of serotonin and its receptors in activation of immune responses and inflammation. Acta Physiologica 213, 561-574, 2105.

Shajib, M.S., Baranov, A. and Khan, W.I. Diverse effects of gut-derived serotonin in intestinal inflammation. American Chemical Society Chemical Neuroscience 8, 920-931, 2017.

Solanas, M. and Escrich, E. An improved protocol to increase sensitivity of Southern blot using dig-labelled DNA probes. Journal of Biochemical and Biophysical Methods 35, 153-159, 1997.

Sprent, J., Zhang, X., Sun, S. and Tough, D. T-cell proliferation in vivo and the role of cytokines. Philosophical Transactions of The Royal Society B-Biological Sciences 355, 317-322, 2000.

Stillie, R. and Stadnyk, A.W. Role of TNF receptors, TNFR1 and TNFR2, in dextran sodium sulfate-induced colitis. Inflammatory Bowel Diseases 15, 1515-1525, 2009.

Sun, H.S., Su, I.J., Lin, Y.C., Chen, J.S. and Fang, S.Y. A 2 center dot 6 Mb interval on chromosome 6q25.2-q25.3 is commonly deleted in human nasal natural killer/T-cell lymphoma. British Journal of Haematology 122, 590-599, 2003.

Taylor, C.R. and Levenson, R.M. Quantification of immunohistochemistry--issues concerning methods, utility and semiquantitative assessment II. Histopathology 49, 411-424, 2006.

Teng, M.W., Andrews, D.M., McLaughlin, N., von Scheidt, B., Ngiow, S.F., Möller, A., Hill, G.R., Iwakura, Y., Oft, M. and Smyth, M.J. IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. Proceedings of the National Academy of Sciences of the United States of America 107, 8328-8333, 2010.

Tenpenny, R.C. and Commons, K.G. What Gene Mutations Affect Serotonin in Mice? ACS Chemical Neuroscience 8, 987-995, 2017.

Ullman, T.A. and Itzkowitz, S.H. Intestinal inflammation and cancer. Gastroenterology 140, 1807-1816, 2011.

Varela, M.L., Mogildea, M., Moreno, I. and Lopes, A. Acute inflammation and metabolism. Inflammation 41, 1115-1127, 2018.

Vasquez, K.O., Casavant, C. and Peterson, J.D. Quantitative whole body biodistribution of fluorescent-labeled agents by non-invasive tomographic imaging. Public Library of Science One 6, e20594, 2011.

Wan, M., Ding, L., Wang, D., Han, J. and Gao, P. Serotonin: a potent immune cell modulator in autoimmune diseases. Frontiers in Immunology 11, 186, 2020.

Wang, D. and Dubois, R.N. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene 29, 781-788, 2010.

Wang, G., Wang, Q., Liang, N., Xue, H.Y., Yang, T., Chen, X.G., Qiu, Z.Y., Zeng, C., Sun, T., Yuan, W.T., Liu, C.X., Chen, Z.Q. and He, X.L. Oncogenic driver genes and tumor microenvironment determine the type of liver cancer. Cell Death and Disease 11, 313, 2020.

Wang, K. and Karin, M. The IL-23 to IL-17 cascade inflammation-related cancers. Clinical and Experimental Rheumatology 33, 87-90, 2015.

Watnick, R.S. The role of the tumor microenvironment in regulating angiogenesis. Cold Spring Harbor Perspectives in Medicine 2, a006676, 2012.

Weiner, H.L. and Selkoe, D.J. Inflammation and therapeutic vaccination in CNS diseases. Nature 420, 879-884, 2002.

Wong, R.W.J., Ngoc, P.C.T., Leong, W.Z., Yam, A.W.Y., Zhang, T., Asamitsu, K., Iida, S., Okamoto, T., Ueda, R., Gray, N.S., et al. Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia. Blood 130, 2326-2338, 2017.

Wu, D., Wu, P., Huang, Q., Liu, Y., Ye, J. and Huang, J. Interleukin-17: a promoter in colorectal cancer progression. Clinical and Developmental Immunology 1, 436307, 2013.

Yen, W.H., Ke, W.S., Hung, J.J., Chen, T.M., Chen, J.S. and Sun, H.S. Sp1-mediated ectopic expression of T-cell lymphoma invasion and metastasis 2 in hepatocellular carcinoma. Cancer Medicine 5, 465-477, 2016.

Yilmaz, M. and Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer and Metastasis Reviews 28, 15-33, 2009.

Zeng, D., Li, M., Zhou, R., Zhang, J., Sun, H., Shi, M., Bin, J., Liao, Y., Rao, J. and Liao, W. Tumor microenvironment characterization in gastric cancer identifies prognostic and immunotherapeutically relevant gene signatures. Cancer Immunology Research 7, 737-750, 2019.

Zhao, R., Liang, H., Clarke, E., Jackson, C. and Xue, M. Inflammation in chronic wounds. International Journal of Molecular Sciences 17, 2085, 2016.

Zondag, G.C.M., Evers, E.E., ten Klooster, J.P., Janssen, L., van der Kammen, R.A. and Collard, J.G. Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. Journal of Cell Biology 149, 775-781, 2000.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2020-12-10起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2020-12-10起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw