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系統識別號 U0026-2906202017254400
論文名稱(中文) 痛風與大腸直腸癌之相關研究
論文名稱(英文) The Study of Association between Gout and Colorectal Cancer
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 108
學期 2
出版年 109
研究生(中文) 莊仁賓
研究生(英文) Jen-Pin Chuang
學號 S98991097
學位類別 博士
語文別 英文
論文頁數 51頁
口試委員 指導教授-李政昌
指導教授-呂增宏
口試委員-張金堅
口試委員-陳鴻華
口試委員-馬明琪
召集委員-呂佩融
口試委員-洪澤民
口試委員-江伯敏
口試委員-張定宗
中文關鍵字 大腸直腸癌  細胞凋亡酶-1  表皮生長因子受體途徑受質No.8  痛風  發炎體  尿酸單鈉  巨噬細胞  國家健康保險研究數據庫 
英文關鍵字 Colorectal cancer  Caspase-1  Eps8  Gout  Inflammasome  Monosodium urate  Macrophages  National Health Insurance Research Database 
學科別分類
中文摘要 目的﹕大腸直腸癌(CRC)是全球第三大最常被診斷的癌症。痛風是由關節中的尿酸單鈉鹽(MSU)晶體吞噬作用引起的炎性關節炎,據估計,這種疾病影響約5%的世界老年人和中年人口。介白素-1β 是痛風急性炎症反應中的主要細胞激素,含有NOD,LRR和Pyrin 3發炎體 (NLRP3 inflammasome) ,為細胞凋亡酶-1(caspase-1)活化所必需的反應平台,caspase-1激活與介白素1β的產生有關。caspase-1激活的潛在機制尚不清楚。本研究的第一部分旨在通過一項針對全國性人群的世代研究來確定痛風患者產生大腸直腸癌的風險,該人群包括台灣痛風患者和普通人群。在第二部分中,我們證明了表皮生長因子受體途徑受質No.8(Eps8)在不依賴NLRP3 inflammasome的caspase-1激活途徑中扮演必要的誘導角色。
材料與方法﹕從台灣國家健康保險研究數據庫中,我們確定了2000-2010年之間新診斷患有痛風的28,061名患者。我們隨機選擇了84,248名性別、年齡和基準年匹配的受試者作為控制組。對該研究族群追蹤,直到大腸直腸癌發生或從國家健康保險系統退出或直到2013年12月31日。針對兩個組之間CRC的累積發生率和發生率比率(IRR)進行了分析,使用Cox比例風險模型評估與CRC發生相關的危險因素。實驗室的研究中,利用沒有完整NLRP3 inflammasome的RAW264.7巨噬細胞,來研究Eps8在MSU晶體介導的caspase-1激活中的作用。
結果﹕在13年的追蹤期內,痛風人群中大腸直腸癌的發生率達到每千人年2.44,高於對照組的每千人年2.13 (IRR = 1.15; 95%CI 1.04至1.26)。在控制了年齡,性別,城市化狀況和合併症(包括高血壓,糖尿病和高脂血症)之後,痛風顯示出與大腸直腸癌風險增加無顯著相關性 (校正後的HR = 1.03; 95%CI 0.93至1.14)。實驗室動力學研究顯示,在RAW 264.7細胞中,MSU晶體對Eps8表現誘導發生在NLRP3,p46 / p33 caspase-1和成熟介白素-1β之前。此外,肌動蛋白(actin)細胞骨架動力學(cytoskeleton dynamic)是MSU晶體刺激過程中Eps8誘導和caspase-1激活所必需的。透過基因沉默Eps8對p46 / p33 caspase-1和NLRP3的基準表現量沒有影響,但幾乎消除了MSU晶體誘導的NLRP3表達和caspase-1的激活。此外,MSU晶體誘導形成Eps8–pro-caspase-1複合物,而Eps8與p33 caspase-1形成穩定的複合物,而非與NLRP3形成複合物。
結論﹕在台灣,有痛風和無痛風的患者發生大腸直腸癌的風險相似。在台灣,別嘌醇(allopurinol)和秋水仙素(Colchine)通常被用為降低尿酸的藥物和消炎藥,並已被證明可以降低大腸直腸癌發生的風險。因此,需要更進一步的藥物流行病學研究,以明確評估別嘌呤醇在痛風與CRC之間的關係。我們的實驗室結果首次證明了在MSU晶體介導下,Eps8在沒有NLRP3發炎體的參與下,對caspase-1激活的重要性。
英文摘要 Purposes: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Gout is an inflammatory arthritis caused by the phagocytosis of monosodium urate (MSU) crystal deposition in joints that is estimated to affect approximately 5% of the world’s elderly and middle-age population. NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome-dependent caspase-1 activation is implicated in the processing of interleukin-1β (IL-1β), which is the major effector cytokine in the acute inflammatory response of gout. Mechanisms underlying caspase-1 activation remain unclear. The first part of the study, we aimed to determine CRC risks among patients with gout through a follow-up study on a nationwide population-based cohort that included patients with gout and the general population in Taiwan. In the second part, we demonstrated the essential role of epidermal growth factor receptor pathway substrate no. 8 (Eps8) induction in the NLRP3-inflammasome-independent caspase-1 activation pathway.
Materials and Methods: From the Taiwan National Health Insurance Research Database, we identified 28,061 patients who were newly diagnosed with gout between 2000 and 2010 as the study cohort. We randomly selected 84,248 subjects matching in gender, age and baseline year as comparison cohort. The cohorts were followed up until CRC occurrence, withdrawal from the system of National Health Insurance, or Dec. 31, 2013. Cumulative incidences and incidence rate ratios (IRRs) of CRC between two cohorts were examined. The Cox proportional hazards model was used to evaluate risk factors associated with CRC development. RAW264.7 macrophages that have no intact NLRP3 inflammasomes were used to investigate the role of Eps8 in MSU crystal-mediated caspase-1 activation.
Results: During the 13-year follow-up, the incidence rate of CRC development in the gout cohort reached 2.44 per 1000 person-years, which was higher than the 2.13 per 1000 person-years in the control cohort (IRR=1.15; 95% CI 1.04 to 1.26). After adjusting for age, gender, urbanisation status and comorbidities, including hypertension, diabetes and hyperlipidaemia, gout showed no significant association with increased risk of CRC occurrence (adjusted HR=1.03; 95% CI 0.93 to 1.14). A kinetic study revealed that the induction of Eps8 expression by MSU crystals occurred before NLRP3, p46/p33 caspase-1, and mature IL-1β in RAW 264.7 cells. In addition, actin cytoskeleton dynamics was required for Eps8 induction and caspase-1 activation in MSU crystal stimulation. Silencing Eps8 had no effect on the basal expression of p46/p33 caspase-1 and NLRP3, but nearly abolished MSU crystal-induced NLRP3 expression and caspase-1 activation. Furthermore, MSU crystals induced Eps8–pro-caspase-1 complex formation and Eps8 formed a stable complex with p33 caspase-1, but not with NLRP3
Conclusion: Similar risks of CRC incidence were observed in patients with and without gout in Taiwan. Allopurinol and colchicine are commonly used as urate lowering drug and anti-inflammation medication in Taiwan and had been shown to reduce the risk of CRC incidence. Thus, further pharmaco-epidemiological studies should be carried out to specifically assess the role of allopurinol in the relationship between gout and CRC. Our laboratory results demonstrated for the first time the importance of Eps8 in MSU crystal-mediated caspase-1 activation without the involvement of NLRP3 inflammasomes.
論文目次 Abstract…………...……………………………………………………………. I
Abstract in Chinese……………………………………………………………. III
Acknowledgement…………………………………………………………....... V
Table of Contents…………………………………………………………........ VII
List of Tables………………………………………………………………....... X
List of Figures………………………………………………………………….. XI
Abbreviations…………………………………………………………….......... XII
Chapter I The Association of Gout and Colorectal Cancer………………… 1
1 Background & objectives…………………………………………………1
2 Literature Review………………………………………………………….2
2.1 Gout Epidemiology and Clinical Manifestation…………………………2
2.2 Epidemiology and pathophysiology of Colorectal Cancer ….…………..2
2.3 The Association between Gout and Colorectal Cancer……...…………..3
3 Materials and Methods…………………………………………………….4
3.1 Data Sources…………………………………………………………….4
3.2 Study cohort……………………………………………………………..5
3.3 Statistical analysis……………………………………………………….6
4 Results………………………………………………………………………7
4.1 The gout cohort was susceptible to metabolic syndromes……….............7
4.2 CRC cumulative rate was higher in patients with gout than in non-gout controls…………………………………………………………………..7
4.3 Patients with gout diagnosis showed no association with significantly
increased risk of CRC…………………………………………………...8
5 Discussion…………………………………………………….9
5.1 The largest nationwide study in Taiwan to investigate the association between gout and subsequent risks of CRC…………………………….9
5.2 Strengths and limitations of the study association between gout and CRC…………………………………………………………………….10
5.3 Inflammatory condition increased the risk for CRC development……...11
5.4 The potential protective effect of allopurinol and colchicine use in CRC development for patients with gout……………………………………...11
Chapter II The role of Eps8 in the process of caspase-1 activation in MSU _stimulated macrophages………………………………….…….14
1 Background & objectives………………………………………………….14
2 Literature Review………………………………………………………….14
2.1 Gout pathophysiology……………………………………………………14
3 Materials and Methods……………………………………………………16
3.1 Reagents and antibodies …..…………………………………………….16
3.2 Cell culture and lysate preparation……………………………………..17
3.3 Western blotting and immunoprecipitation…………………………......17
3.4 RNA interference……………………………………………………….17
4 Results………………………………………………………………………18
4.1 MSU crystals induce Eps8 expression before the induction of NLRP3 and the activation of caspase-1 in RAW 264.7 cells…..………...………18
4.2 Actin cytoskeleton dynamics regulates MSU crystal-induced Eps8 expression and caspase-1 activation in RAW 264.7 cells……………….19
4.3 Eps8 is required for caspase-1 activation in MSU crystal-treated RAW264.7cells…..……………………………………………………20
4.4 MSU crystals enhance the complex formation between Eps8 and
caspase-1 but not NLRP3 in RAW 264.7 cells………………………….21
5 Discussion…………………………………………………….22
5.1 The potential role of Eps8 in the gout inflammation process…………...22
5.2 Eps8–caspase-1 complexes are functional in mediating IL-1β cleavage in response to MSU crystal stimulation………………………………....22
5.3 FBS may provide a priming signal to facilitate Eps8-mediated caspase-1 activation in RAW264.7 macrophages.………………………23
5.4 Actin cytoskeleton dynamics is critical in MSU crystal-stimulated caspase-1 activation……………………………………………………. 24
Chapter III Summary and Conclusion...……………………………….……. 26
References……………………………………………………………………… 27
Tables…………………………………………………………………………… 33
Figures…………………………………………………………………………. 37
Related Publications…………………………………...……………………… 50
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