臺灣博碩士論文加值系統

犬傳染性花柳性腫瘤(canine transmissible venereal tumor; CTVT)為一可用來研究腫瘤與宿主免疫系統交互作用之腫瘤模式。此腫瘤具有明顯的腫瘤分期，其會持續的生長一段時間（P期)，繼而自行消退 (R期)。在此過程中，複雜之基因調控網絡自然無可避免的參與其中。先前我們發現犬chitinase 3-like 1(CHI3L1)基因在R期時之表現量明顯高於P期。由於CHI3L1一般被認為與腫瘤惡化及癌症預後不佳有關，因此我們想了解犬CHI3L1於CTVT生長過程中所扮演的角色。在本次研究中，完整的犬CHI3L1基因首次被成功從CTVT以及巨噬細胞中選殖出來，比較兩者後發現CTVT之CHI3L1沒有突變產生。在經過氨基酸序列比對、蛋白質結構預測，以及肝素親合性試驗後，我們證實犬CHI3L1為一分泌型蛋白，對肝素具有親和性，且可能如同人的CHI3L1具有促進免疫反應的能力。此外，藉由纖維母細胞增生試驗，我們也發現犬之CHI3L1可刺激纖維母細胞之增生。目前已知CHI3L1可參與腫瘤生長過程、血管新生成效應以及自體免疫反應。而在CTVT R期高量表現之犬CHI3L1，可能與抗腫瘤之免疫反應或是腫瘤及腫瘤微環境間的交互作用有關。本研究旨在初步探討犬CHI3L1之基因組成與功能分析，希望可以在腫瘤研究及治療上提供新的想法與方向。

Canine transmissible venereal tumor (CTVT) is a unique tumor model for studying tumor/host immunity interaction. A progressive growing stage (P phase) followed by tumor regression (R phase) is the typical trait of this tumor with which a complicated gene-expressing network is involved to regulate tumor progression or remission. Previously, the canine chitinase 3-like 1 (CHI3L1) gene was found up-regulated in R phase CTVT. Since CHI3L1 is now mostly considered to relate to tumor malignancy or poor prognosis, we intend to inspect the role of canine CHI3L1 in CTVT. In this study, the full canine CHI3L1 gene was cloned for the first time from CTVT and normal canine macrophages to reveal that no mutations were generated in tumor specimens. By alignment with CHI3L1 from other species, protein structural and functional prediction, and in vitro protein expression followed by heparin-binding bioassay, the results indicated that canine CHI3L1 is a secretory protein with heparin-binding activity and may promote immune responses against CHI3L1. Furthermore, similar to its human homologue, canine CHI3L1 also stimulated proliferation of fibroblast cells. Taken together, CHI3L1 is a multi-functional protein known to play roles in tumor progress, autoimmune diseases, and angiogenesis. Overexpression of canine CHI3L1 in regressed CTVT may disclose associations with anti-tumor immunity or interplay between tumors and their microenvironment. Characterization of canine CHI3L1 in our study has provided new inspiration for investigating cancer biology and therapy.

Contents
致謝 I
中文摘要 III
Abstract IV
Chapter 1. Background and Literature Review 1
1.1 Canine transmissible venereal tumor (CTVT) 1
1.1.1 Identification of CTVT 1
1.1.2 Progress of CTVT 2
1.1.3 Relationaship between anti-tumor immunity and spontaneous regression in CTVT 2
1.2 Chitinase 3-like 1 (CHI3L1) 3
1.2.1 Expressions and regulations of CHI3L1 gene 4
1.2.2 Structure to function relationship 5
1.2.3 Biologic activities of CHI3L1 7
1.2.4 The relationship between CHI3L1 and diseases 8
1.2.4.1 CHI3L1 in autoimmune diseases 8
1.2.4.1.1 RA pathogenesis related to CHI3L1 9
1.2.4.1.2 OA and IBD pathogenesis related to CHI3L1 10
1.2.4.2 CHI3L1 in cancers 11
1.2.4.3 CHI3L1 in other diseases 12
1.3 Conclusion 12
Chapter 2. Introduction 13
Chapter 3. Materials and methods 16
3.1 Animals 16
3.2 Tumor model 16
3.3 Generation of canine macrophages 16
3.4 RT-PCR 17
3.5 Computational analysis 18
3.6 Expression of canine CHI3L1 in BALB/3T3 cells 18
3.7 Western blot analysis 18
3.8 Indirect immunofluorescence assay (IFA) 19
3.9 Flow cytometric analysis 19
3.10 Protein identification 20
3.11 Heparin-Sepharose affinity assay 21
3.12 Fibroblast proliferation assay 21
3.13 Statistical analysis 21
Chapter 4. Results 23
4.1 Molecular cloning of canine CHI3L1 gene 23
4.2 Structural and functional prediction 23
4.3 Eukaryotic expression of canine CHI3L1 24
4.4 Protein identification analysis 25
4.5 Bioactivity assay 25
Chapter 5. Discussion 27
Figure 32
Fig. 1. Diagrams for interpreting primer design and RT-PCR method. 32
Fig. 2. RT-PCR of and sequencing data of canine CHI3L1, also the alignments with other species. 33
Fig. 3. Canine CHI3L1 structural and functional prediction. 34
Fig. 4. Canine CHI3L1 protein expression and analysis. 36
Fig. 5. Protein identification. 39
Fig. 6. Bioactivity of canine CHI3L1. 41
Reference 43

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