臺灣博碩士論文加值系統

胰臟癌是目前在全球癌症致死率中排名第七名的癌症，且相較於其他的常見癌症，胰臟癌有著最低的五年存活率。這主要的原因來自於難以早期診斷來及時治療癌症，約有85%的胰臟癌病人在確診時已進展到無法手術切除的癌症末期。因此，發展出早期診斷胰臟癌是很重要的事情。雖然胰臟癌的症狀在初期往往不明顯的，確診通常已經是晚期。然而許多研究指出糖尿病是胰臟癌的危險因子，並且根據統計，其中約有40%胰臟癌病人在診斷前三年便患有糖尿病的病癥，而那我們將這種新生糖尿病稱之為胰臟癌誘發之糖尿病。藉由鑑定新穎的胰臟癌誘發糖尿病的生物標記並釐清其中的機制可能提供早期診斷胰臟癌的線索。
胰臟癌誘發之糖尿病被認為是胰臟癌會分泌出一些未知的致糖尿病因子進而促進全身的胰島素阻抗。藉由蛋白質體學和生物資訊學的分析，我們從胰臟癌細胞株的條件培養基中鑑定出galectin-3這個候選蛋白。我們進一步證明重組galectin-3能顯著抑制C2C12骨骼肌肉細胞的葡萄糖攝取能力。根據上述的結果與分析，我們假設galectin-3在胰臟癌誘發之糖尿病可能扮演著致糖尿病因子的角色。首先為了評估galectin-3作為其生物標記的能力，我們收集並檢測了不同病人族群血清中galectin-3的濃度，結果顯示胰臟癌誘發之糖尿病相對於其他癌症有著最高的galectin-3表現量，透過ROC曲線分析可以得到galectin-3能有效區分胰臟癌誘發之糖尿病和第二型糖尿病或其他病人族群。我們進一步將galectin-3和其他參數指標合併，可以得到更好的鑑別力。
除此之外，我們深入探討是否重組蛋白galectin-3能透過抑制肌肉細胞的胰島素訊息傳遞路徑來促進胰島素阻抗。我們結果發現galectin-3會促進抑制性IRS-1的絲氨酸307號位點的磷酸化，並抑制下游AKT的活化來阻抗胰島素的訊息傳遞。接著，我們發現重組蛋白能直接與細胞的TLR4產生交互作用。同時galectin-3也能活化TLR4典型的下游訊息途徑 ─ IKK-β/NF-κB的訊息傳遞，而IKK-β已被報導會促進IRS-1絲氨酸307號位點的磷酸化。除此之外，TLR4抑制劑能部份地回復galectin-3誘導之胰島素阻抗，顯示galectin-3藉由結合TLR4來抑制胰島素訊息傳遞。
另一方面，實驗室前人研究指出galectin-3會抑制胰島β細胞的胰島素釋放。這暗示著galectin-3可能也透過抑制胰島素釋放來造成代謝性失調。我們的結果顯示胰臟癌細胞株的條件培養基與galectin-3能抑制胰島細胞的存活率，而caspase 3活性與TUNEL試驗進一步證明galectin-3能促進胰島細胞的細胞凋亡。同樣地，TLR4抑制劑能部份地回復galectin-3誘導之細胞凋亡，暗示galectin-3藉由結合TLR4來誘導胰島細胞的細胞凋亡。
綜上所述，此篇研究試圖了解glaectin-3如何透過細胞層次的訊息傳遞來造成系統的胰島素阻抗和胰島細胞死亡，進而支持galectin-3在胰臟癌誘發之糖尿病扮演著致糖尿病因子的角色。到目前為止，我們的結果也證實galectin-3是一個有潛力作為胰臟癌誘發之糖尿病的診斷型生物標記，在未來可透過研究出此疾病有效的複合型生物標記來做為早期診斷出胰臟癌的策略。

Pancreatic cancer (PC) is the seventh leading cause of cancer-related deaths in the world with the lowest 5-year survival rate among other common cancers. Due to the lack of methods for early detection, 85% pancreatic cancer are diagnosed at unresectable/advanced stage. Therefore, it is the urgent need for detecting PC at early stage. Although PC patients are usually physically asymptotic until tumors deteriorated, numerous evidences indicated diabetes mellitus (DM) is a risk factor for PC, and 40% PC patients had developed DM in the 36 months preceding the diagnosis of PC, called pancreatic cancer-associated diabetes mellitus (PCDM). Identification of PCDM by novel biomarkers and elucidating the underlying mechanism may provide the potential clue to achieve the early detection of PC.
The model of PCDM induction is proposed that PC secretes some unknown diabetogenic factors to promote systemic insulin resistance. By combining proteomic analysis and bio-informatics screening, our previous studies identified galectin-3 as a candidate in the conditioned medium of PC cell lines. Moreover, recombinant galectin-3 decrease glucose uptake of C2C12 myotubes in vitro. Based on the results above, we assumed galectin-3 may be a diabetogenic factor in PCDM. To evaluate the efficacy of galectin-3 as a PCDM biomarker, we detected the serum of different groups’ patients, and PCDM serum showed the highest galectin-3 expression among other patients’ serum. ROC curve indicated galectin-3 expression is able to distinguish PCDM from T2DM or other diseases. Moreover, combinations of galectin-3 and different parameters could elevate the ability of discriminating PCDM from T2DM.
Besides, we further investigated whether extracellular galectin-3 affected insulin signaling of C2C12 myotubes. Our data found extracellular galectin-3 attenuated insulin signaling by increasing the inhibitory serine phosphorylation of IRS-1 and decreasing the activated phosphorylation of AKT. Next, we showed recombinant galectin-3 can interact with TLR4 directly by immunoprecipitation. Notably, galectin-3 activated the IKK-β/NF-κB pathway as the canonical downstream pathway of TLR4, and IKK-β was reported to promote IRS-1 inhibitory phosphorylation. In addition, galectin-3-mediated insulin resistance was partially rescued by TLR4 inhibitor treatment, suggesting galectin-3 inhibited insulin signaling through TLR4.
On the other hand, we found galectin-3 decreased insulin secretion in β cells. It suggested galectin-3 may have alternative functions to cause metabolic dysfunction by inhibiting β cells’ insulin secretion. In our results, we found conditioned medium of PC cell line and recombinant galectin-3 decreased the cell viability. Furthermore, caspase 3 activity and TUNEL assay were confirmed that galectin-3 can promote β cells’ apoptosis. Similarly, TLR4 inhibitor treatment was assessed and galectin-3-mediated apoptosis was partially rescued, suggesting TLR4 was involved in galectin-3-mediated apoptosis of β cells.
Taken together, this study sought to understand how galectin-3 promotes systemic insulin resistance and destruction of β cells in cellular signaling level, further to support galectin-3 plays a diabetogenic role in PCDM. So far, our results also verify galectin-3 is a potential diagnostic biomarker for PCDM, and in the future, to find reliable diagnostic biomarker panels for PCDM is a feasible strategy to achieve early detection of pancreatic cancer.

Contents
中文摘要 i
Abstract iii
Abbreviation v
Contents viii
List of figures xiii
List of supplements xiv
Chapter I ─ Overview and Introduction 1
1.1. Introduction to Pancreatic Cancer (PC) 1
1.1.1 Epidemiology of pancreatic cancer 1
1.1.2 The types of pancreatic cancer 2
1.1.3 The symptoms of pancreatic cancer 2
1.1.4 Risk Factors of Pancreatic cancer 3
1.1.5 Diagnosis and Treatment 4
1.2. Overview of Pancreatic Cancer-Associated Diabetes Mellitus (PCDM) 5
1.2.1 Definition of PCDM 5
1.2.2 Mechanism of PCDM 6
1.3 Overview of Insulin resistance and insulin secretion 7
1.3.1 Insulin signaling 7
1.3.2 Insulin resistance 7
1.3.3 insulin secretion of β cells 9
1.3.4 β cells dysfunction and Type 2 diabetes mellitus 10
1.4 Overview of Biomarker 10
1.4.1 Definition of biomarker 10
1.4.2 Tumor biomarkers 10
1.4.3 Pancreatic cancer biomarker 11
1.4.4 The Challenges and Opportunities of Pancreatic Cancer 11
1.5 The Characteristics and Functions of Galectin-3 12
1.5.1 Characteristics of Galectin 12
1.5.2 Galectin ─ Glycan interaction and extra/intracellular signaling of galectins 13
1.5.3 The characteristic of galectin-3 13
1.5.4 Extracellular functions of galectin-3 14
1.6 Specific aims 15
Chapter II Experiment Materials 17
2.1 Cell line 17
2.2 Serum Sample 17
2.3 Primary Antibody 17
2.4 Secondary Antibody 18
2.5 Reagents 18
2.6 Kits 20
2.7 Instruments 21
Chapter III Experiment Methods 22
3.1 Cell culture 22
3.1.1 Cell Subculturing 22
3.1.2 Medium for culturing: 22
3.1.3 Differentiation of C2C12 myotube formation 22
3.2 Candidate preparation, selection and identification 23
3.2.1 Expressions of recombinant candidate proteins 23
3.2.2 Purification of recombinant candidate proteins 23
3.2.3 Harvest of conditioned medium (CM) from MIA PaCa-2 cell 23
3.2.4 The Cancer Genome Atlas (TCGA) analysis 24
3.2.5 Patients and measurement of factor serum levels 24
3.3 Protein Analysis 25
3.3.1 Quantification of concentration of proteins 25
3.3.2 Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) 25
3.3.3 Coomassie Brilliant Blue (CBB) staining 26
3.3.4 Immunoblotting analysis 27
3.4 Functional assay 27
3.4.1 Measurement of glucose uptake 27
3.4.2 Immunohistochemistry 28
3.4.3 Immunoprecipitation assay 28
3.4.4 MTT assays for Cell viability. 28
3.4.5 Insulin secretion 29
3.4.6 Sandwich Enzyme-linked immunosorbent assay (ELISA) 29
3.4.7 Ca2+ Measurements 30
3.4.8 Flow cytometry for Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. 30
3.5 Statistical analysis 30
Chapter IV Results 32
4.1 Identification and validation of potential diabetogenic (PCDM) factors in MIAPaCa-2 conditioned medium. 32
4.2 Effects of galectin-1, TIMP-1, galectin-3 on insulin-stimulated glucose uptake in C2C12 myotubes. 32
4.3 Elucidating serum galectin-3’s concentration and Discrimination ability for PCDM patients. 33
4.4 Receiver operating characteristic (ROC) curves for discriminating between PCDM and T2DM in combination of different parameters 34
4.5. Investigating the mechanism of galectin-3-mediated insulin resistance in insulin signaling pathway of C2C12 myotubes. 35
4.5.1 Understanding the insulin signaling pathway involved in galectin-3-mediated insulin resistance. 35
4.5.2 Galectin-3 inhibited insulin signaling pathway through TLR4 partially. 36
4.6 Exploring the effects and mechanism of galectin-3-induced apoptosis in INS-1 β islet cells. 36
Chapter V Discussions 38
5.1 Biological functions and clinical relevance of galectins 38
5.1.1 The role of extracellular galectin-3 in cancer progression 38
5.1.2 The role of extracellular galectin-3 inT2DM 38
5.2 Discovering potential PCDM biomarkers for early detection of PC 39
5.2.1 The strategies for screening PC 39
5.2.2 Perspective of multiple biomarker panels for PCDM 41
5.3 Exploring the role of galectin-3 in insulin resistance of PCDM 43
5.3.1 Understanding the mechanism of galectin-3-mediated insulin resistance in PCDM. 43
5.3.2 The regulators of insulin resistance in PCDM 44
5.4 Exploring the roles of galectin-3 in insulin secretion of β islet cells 45
5.4.1 The roles of galectin-3 in pro-apoptosis 45
5.4.2 PC-derived diabetogenic factors cause Beta cell’s apoptosis 46
5.4.3 Galectin-3 promotes apoptosis in INS-1 through TLR4 partially. 46
Chapter VI References 48
Figures 57
Supplements 69

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