臺灣博碩士論文加值系統

YKL-40是一種分泌型的醣蛋白，其生物學功能尚未完全清楚，可能參與了血管生成和細胞外基質重塑，且高血清YKL-40量已經在多種人類炎症性疾病以及惡性腫瘤中被發現。以往的研究還顯示出，在癌症患者中，高血清YKL-40量在不同類型癌症中，有潛力做為與疾病預後不良和短生存時間有關的生物指標，因此，瞭解YKL-40在癌症中的作用機制非常重要。然而，大部分YKL-40於癌症的研究都在人類實體腫瘤進行，對於犬癌症的研究極少；我們先前的研究發現，罹患癌症犬隻的血清YKL-40顯著高於健康犬，且在經過治療後復發的淋巴瘤犬血清中YKL-40高於未復發的犬隻。為了研究YKL-40在犬癌症中的生物學作用，我們在本研究中純化了重組犬YKL-40 (rcYKL-40)，並將其應用於犬淋巴瘤細胞株CLBL-1 (B細胞) 和UL-1 (T細胞)，以評估其對犬淋巴瘤細胞的生物學功能的影響及其背後可能的細胞內信號傳遞途徑。研究結果顯示，包括外周血液淋巴細胞、單核球細胞、單核球來源巨噬細胞及成熟的單核球來源樹突細胞在內的多種犬血液細胞均會表現YKL-40，而未成熟的單核球來源樹突細胞和犬淋巴瘤細胞CLBL-1和UL-1則不表現；在細胞實驗中，rcYKL-40促進了UL-1細胞的增殖和遷移能力，但僅增進了CLBL-1細胞的侵襲能力，我們推測這是由於CLBL-1原本就生長較快，rcYKL-40無法更加促進其增殖與遷移的能力。此外，在細胞活力存活試驗中發現，化療藥物阿黴素可以有效抑制CLBL-1和UL-1的增殖，而給予rcYKL-40可以保護兩種細胞減少阿黴素的傷害，並提高細胞存活率。透過細胞內信號途徑分析結果可得知，經rcYKL-40處理後，CLBL-1的ERK和UL-1的AKT磷酸化蛋白的活性均增加，未來可以更深入探索YKL-40作用的分子機制，以及將YKL-40作為治療犬淋巴瘤潛在標靶的治療策略。

YKL-40 is a glycoprotein with incompletely understood biological functions. It was suggested to be involved in angiogenesis and extracellular matrix remodeling. Increased serum concentrations of YKL-40 have been detected in various human inflammatory diseases and malignancies. Previous studies also showed elevated serum levels of YKL-40 in cancer patients could be a potential biomarker that is associated with poor prognosis and short survival time in different kinds of cancer. Therefore, it’s important to clarify how YKL-40 plays in cancers. However, most of the YKL-40 studies on cancer are based on human solid tumors. There are few studies on canine cancers. Our previous studies found that the serum YKL-40 level in cancer dogs had a substantial elevation compared to healthy dogs. Additionally, serum YKL-40 level in lymphoma dogs who relapsed after treatment was higher than without relapse. To investigate the biological functions of YKL-40 in dog cancer, recombinant canine YKL-40 (rcYK-40) was purified and applied to canine lymphoma cells, CLBL-1 (B cell) and UL-1 (T cell), in this study. The results show various canine blood cells including peripheral blood lymphocytes, monocytes, monocyte-derived macrophages, and mature monocyte-derived dendritic cells express YKL-40, whereas immature monocyte-derived dendritic cells and both CLBL-1 and UL-1, do not. In the cellular assay, the rcYKL-40 promotes the abilities of proliferation and migration on UL-1 cells, while it only elicits the invasion ability of CLBL-1 cells. Besides, in viability assay, doxorubicin (DOX) effectively inhibits the proliferation of CLBL-1 and UL-1. However, the administration of rcYKL-40 protects both cells from DOX damage and increases cell survival. By treating with the rcYKL40, the phosphorylation activity of ERK in CLBL-1 and AKT in UL-1 increased. Co-treatment of DOX and rcYKL40 on UL-1, but not CLBL-1, the activity of both proteins was also increased. These imply the potential role of YKL-40 on cellular processes and DOX-induced damage in canine lymphoma. Further studies may explore the molecular mechanisms of YKL-40 and potential therapeutic strategies targeting YKL-40 in canine lymphoma treatment.

誌謝 i
中文摘要 ii
Abstract iii
Chapter 1. Background and Literature Reviews 1
1.1 YKL-40 1
1.1.1 Expressions and regulations of YKL-40 2
1.1.2 The prognostic value of YKL-40 in inflammatory diseases and cancers 3
1.1.3 The correlation between YKL-40 and non-cancer diseases 4
1.1.4 The correlation between YKL-40 and cancers 5
1.1.5 The possible mechanisms of YKL-40 in cancers 6
1.2 Canine lymphoma 8
1.2.1 Incidence and predilection 9
1.2.2 Clinical subclassifications 10
1.2.3 Diagnosis 12
1.2.4 Treatment options 13
1.3 Oncogenic behavior of cancer cells 15
1.3.1 Abnormal proliferation 16
1.3.2 Migration and Invasion 17
1.3.3 Cell death resistance 18
1.4 Conclusion 19
Chapter 2 Introduction 20
Chapter 3. Materials and Methods 23
3.1 Cell cultures 23
3.2 Generation of canine peripheral blood lymphocytes, monocytes, macrophages, and dendritic cells 23
3.3 Expression and purification of recombinant canine YKL-40 protein 25
3.4 Total RNA extraction 26
3.5 RT-PCR 27
3.6 PCR 28
3.7 Genomic DNA extraction 29
3.8 PCR for antigen receptor rearrangements (PARR) 29
3.9 Proliferation assay 30
3.10 Transwell migration assay 31
3.11 Invasion assay 32
3.12 Viability assay 33
3.13 Cell signal pathway analysis 34
3.14 Western blot analysis 35
3.15 Statistical analysis 37
Chapter 4. Results 38
4.1 Examination of YKL-40 expression in various canine cells 38
4.2 Preparation of recombinant canine YKL-40 protein 38
4.2.1 Purification of recombinant canine YKL-40 protein 38
4.2.2 Identification of purified recombinant canine YKL-40 39
4.3 Detection of gene rearrangements in canine lymphoma cell lines 39
4.4 Proliferation assay 40
4.5 Transwell migration assay 40
4.6 Invasion assay 41
4.7 Viability assay 41
4.8 Cell signal pathway analysis 42
4.9 Expression of YKL-40-related receptor 42
Chapter 5. Discussion 43
Tables 54
Table 1. The primers used in this study 54
Figures 55
Figure 1. Experimental design 55
Figure 2. Schematic diagram of the construction of prcYKL-40 56
Figure 3. YKL-40 mRNA expressions of canine lymphoma cell lines and peripheral blood cells 57
Figure 4. Purification of recombinant canine YKL-40 protein (46.7kDa) 58
Figure 5. Detection of gene rearrangements in canine lymphoma cell lines 59
Figure 6. Effect of rcYKL-40 protein on cell proliferation rate 60
Figure 7. Effect of rcYKL-40 protein on cell viability 64
Figure 8. Cell signal pathway under rcYKL-40 and doxorubicin treatment 65
Figure 9. IL13Rα2 mRNA expressions of canine lymphoma cell lines 66
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