臺灣博碩士論文加值系統

半乳糖凝集素-9(galectin-9)屬於具有串聯重複序列(tandem-repeat type)的半乳糖凝集素，最早是在何杰金氏淋巴瘤(Hodgkin’s lymphoma)病人身上發現，過去研究發現半乳糖凝集素-9具有諸多免疫調控的特性，然而，半乳糖凝集素-9在癌症生物學所扮演的角色仍然不清楚。本研究中，我們發現半乳糖凝集素-9在生發中心B細胞型瀰漫性大型B細胞淋巴瘤(Germinal centre B-cell-like diffuse large B cell lymphoma, GCB-DLBCL)中的表現相對於其他類的生發中心B細胞型淋巴瘤(germinal center derived lymphoma)有增加的情形。首先，在非肥胖糖尿病型重症聯合免疫缺陷型小鼠(NOD/SCID mice) 中異體移植(xenograft model) 半乳糖凝集素-9剔除的生發中心B細胞型瀰漫性大型B細胞淋巴瘤細胞株來研究半乳糖凝集素-9在其中所扮演的角色，結果發現，半乳糖凝集素-9剔除的細胞會造成腫瘤生長能力顯著下降。若將半乳糖凝集素-9剔除的細胞株皮下注射於免疫系統嚴重缺陷小鼠( NOD/Lt-scid IL2rγ null mice; NSG mice)中，腫瘤生長能力卻有回復的現象，推測自然殺手細胞(Natural Killer cells, NK cells)可能扮演重要角色。利用anti-ASGM1抗體在非肥胖糖尿病型重症聯合免疫缺陷型小鼠中剔除自然殺手細胞後，則發現半乳糖凝集素-9剔除的腫瘤有部分回復生長的現象。此外，半乳糖凝集素-9剔除也造成腫瘤中自然殺手細胞浸潤的情形較為嚴重。然而，半乳糖凝集素-9剔除並不會造成細胞凋亡(apoptosis)以及影響細胞週期(cell cycle)。另一方面，c-Jun的表現在過去被認為能夠調控腫瘤微環境，而c-Jun在腫瘤中的表現也受到半乳糖凝集素-9的剔除而降低。總結本研究發現由生發中心B細胞型淋巴瘤而來的半乳糖凝集素-9會造成免疫逃避 (immune escape)，導致自然殺手細胞的功能受到嚴重影響。

Galectin-9, a tandem-repeat type galectin, was first identified in patients with a nodular sclerosis type of Hodgkin’s disease. Previous studies demonstrated various regulatory roles of galectin-9 in the immune responses. However, role of galectin-9 in cancer biology remains elusive. Here, we found galectin-9 expression in germinal centre B-cell-like diffuse large B cell lymphoma (GCB DLBCLs) was up-regulated amongst germinal center lymphomas. To determine the role of elevated galectin-9 expression in vivo, we used NOD/SCID xenograft model of GCB DLBCLs. Strikingly, we observed a dramatic reduction of tumor volume and weight in mice receiving galectin-9 knockdown GCB DLBCL cells. Interestingly, knockdown of galectin-9 did not affect the tumorigenicity in NOD scid gamma (NSG) xenograft model, which implied natural killer (NK) cells might be responsible for the reduced tumor size in NOD/SCID mice. Thus, depletion of NK cells was achieved by anti-asGM1 antibody in NOD/SCID mice. As a result, we found partially restored tumorigenicity in NOD/SCID mice engrafted with galectin-9 knockdown GCB DLBCLs after NK cell depletion. Moreover, tumor-infiltrating NK cells were significantly increased in galectin-9-depleted tumors in NOD/SCID mice. In term of molecular mechanisms, knockdown of galectin-9 induces neither apoptosis nor cell cycle arrest in GCB DLBCLs. On the other hand, we found that the level of c-Jun, a regulator in tumor microenvironment, was decreased in galectin-9 knockdown GCB DLBCL tumors. These data suggested that galectin-9 derived from GCB-DLBCL might cause the immune escape through inhibiting NK cell activity.

致謝 1
中文摘要 3
Abstract 4
Abbreviations 6
Table of Contents 8
List of Figures 11
Chapter I Introduction 13
1. Galectins 13
2. Galectin-9 14
3. Germinal Center Reaction 18
4. Germinal Center B-cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL) 21
5. Nature killer cells and tumor immunology 24
1.2 Rationales 29
1.3 Specific aims 30
Chapter 2 Materials and Methods 31
2.1 Cell culture and mice 31
2.2 Human B cell stimulation and mouse immunization 31
2.3 Xenograft model of DLBCL 32
2.4 Generation of lentivirus and infection of GCB DLBCLs 32
2.5 In vivo depletion of NK cells 33
2.6 RNA extraction, reverse transcription and quantitative Real-Time qPCR 33
2.7 Western blotting 35
2.8 Enzyme-linked immunosorbent assay (ELISA) 36
2.9 Flow-cytometric analysis 36
2.10 Antibodies used in this study 37
2.11 Statistics 39
Chapter 3 Results 40
3.1 Aberrant galectin-9 expression in germinal centre derived lymphoma 40
3.2 Galectin-9 promotes tumorigenicity in a xenograft model of GCB DLBCLs 40
3.3 Knockdown of galectin-9 does not induce either apoptosis or cell cycle arrest in GCB DLBCLs 41
3.4 Phosphorylation of Lyn at Tyr 396 was decreased after knockdown of galectin-9 in GCB DLBCLs 42
3.5 Knockdown of galectin-9 reduced the expression of c-Jun and c-Jun related genes in GCB DLBCL xenograft tumour 43
3.6 Knockdown of galectin-9 does not induce apoptosis level or reduce angiogenesis under hypoxia exposure in GCB DLBCLs 44
3.7 Reduction of tumour size after knockdown of galectin-9 might be NK cell dependent 45
3.8 Depletion of NK cells restored the tumorigenicity in mice engrafted with galectin-9-depleted cells 45
3.9 NK cell infiltration was significantly increased in galectin-9-depleted tumours 46
3.10 High affinity IgG production was compromised in Lgals9 deficient mice followed by NP-KLH immunization 47
Chapter 4 Discussions 48
Chapter 5 Figures 53
Chapter 6 References 74

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