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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82601完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 曾秀如(Shiou-Ru Tzeng) | |
| dc.contributor.author | You-Shu Tsai | en |
| dc.contributor.author | 蔡侑書 | zh_TW |
| dc.date.accessioned | 2022-11-25T07:47:35Z | - |
| dc.date.available | 2024-12-31 | |
| dc.date.copyright | 2021-12-30 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-12-24 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82601 | - |
| dc.description.abstract | 惡質症被發現與多種疾病如愛滋病、慢性腎病、癌症皆有關係，其症狀包含持續性的脂肪流失、全身系統性發炎、體重減輕以及肌肉萎縮，是一種多因素代謝綜合症。其中，胰臟癌誘發的惡質症最為常見，與其它腫瘤相比，有近七成的胰臟癌患者於患病後期會被觀察到伴隨發展出惡質症的情形，更有近三成的胰臟癌患者死於惡質症而非腫瘤疾病。然而，目前仍沒有針對早期診斷胰臟癌誘發之惡質症的生物標記。近年來，有文獻指出腫瘤所釋出的發炎因子可能為造成個體肌肉萎縮導致惡質症的原因，於是我們利用胰臟癌細胞株MIA PaCa-2之培養液刺激C2C12小鼠肌肉細胞後，確實可誘發此現象，因此我們推測胰臟癌腫瘤可能會釋出致惡質症的相關因子並具潛力作為將來診斷的生物標記。 首先為找出具潛力之標的，我們將TCGA以及GTEx資料庫中胰臟癌患者腫瘤以及正常人的胰臟組織進行mRNA表現量的比較，再利用Human Protein Atlas排除非分泌型的蛋白後，使用DAVID以及GO軟體分析，發現其中50個胰臟癌高度表現基因在發炎反應中高度富集，且與CCR的結合 (n=13)和TLR的結合 (n=3)兩功能高度相關，此外，過去有文獻表明TLR-4為癌症惡質症的重要上游之一，我們因此利用大數據策略篩選出S100A8和S100A9為致惡質症的潛在候選因子。另外有研究指出S100A8和S100A9主要以共價結合的異二聚體S100A8/A9形式存在於生理條件下，綜合以上結果，我們最終選擇探討S100A8、S100A9和S100A8/A9作為胰臟癌致惡質症的潛在生物標記之潛力。 根據過去的研究，TLR-4藉由活化NF-κB訊息傳遞路徑使下游惡質症相關因子Atrogin-1和 MuRF-1表現量上升進而導致肌肉萎縮．我們利用C2C12肌肉細胞證實S100A8、S100A9和S100A8/A9會造成肌肉萎縮，同時也發現以上三候選因子皆會通過提高p65磷酸化激活NF-κB，使C2C12中的Atrogin-1和 MuRF-1表現量有所提高。 我們也進一步利用ELISA測定檢體中S100A8、S100A9和S100A8/A9之表現量並分析其在臨床上對胰臟癌致惡質症的重要性。發現除S100A9之外，其餘兩個候選分子S100A8和S100A8/A9相較於正常人、胰臟炎患者、胰臟癌患者，其在胰臟癌致惡質症組別的血清中有明顯的上升，且S100A8/A9異二聚體於血清中的平均濃度更達17.5 μg/mL，遠高於目前已知潛在的惡質症生物標記TNF-α 和IL-6 (分別為34.8和184.8 pg/mL)。此外，我們也進一步發現，合併使用血清中S100A8/A9、TNF-α 和IL-6三種潛在生物標記，可獲得比任一單獨使用更佳的區分效果。我們的研究結果表明S100A8/A9可能是一種相當有潛力的胰臟癌致惡質症新型生物標記，並為開發胰臟癌致惡質症早期診斷提供一突破性之契機。 | zh_TW |
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| dc.description.tableofcontents | "謝誌……………………………………………………………………….I 中文摘要………………………………………………………………...II Abstract………………………………………………………………...IV 縮寫……………………………………………………………………..VI 目錄…………………………………………………………………...VIII 表目錄………………………………………………………………...XIV 圖目錄…………………………………………………………………XV 附錄目錄……………………………....…………………………….XVII 第一章 導論……………………………..……………………………- 1 - 第一節 胰臟癌概論..................................................................................- 1 - 1.1 胰臟癌流行病學..................................................................................- 1 - 1.2 胰臟癌的分期、診斷與分類...............................................................- 2 - 1.2-1 胰臟癌的種類.........................................................................................- 2 - 1.2-2 胰臟癌的分期.........................................................................................- 2 - 1.2-3 胰臟癌的診斷.........................................................................................- 3 - 1.3 胰臟癌的成因......................................................................................- 4 - 1.3-1 家族病史.................................................................................................- 4 - 1.3-2 遺傳性突變基因種類.............................................................................- 4 - 1.3-3 糖尿病.....................................................................................................- 4 - 1.3-4 抽菸.........................................................................................................- 4 - 1.3-5 種族.........................................................................................................- 5 - 1.3-6 肥胖.........................................................................................................- 5 - 1.3-7 胰臟炎.....................................................................................................- 5 - 1.3-8 年齡.........................................................................................................- 5 - 1.3-9 飲食習慣.................................................................................................- 5 - 1.3-10 酒精.......................................................................................................- 5 - 1.4胰臟癌的病徵.....................................................................................- 5 - 1.5胰臟癌的治療.....................................................................................- 6 - 第二節 惡質症概論.................................................................................- 6 - 2.1 惡質症流行病學........................................................................................- 6 - 2.2惡質症的分期及診斷.................................................................................- 6 - 2.3 惡質症的成因.............................................................................................- 7 - 2.3-1 癌症.........................................................................................................- 7 - 2.3-2 慢性阻塞性肺病 (chronic obstructive pulmonary disease, COPD).......- 7 - 2.3-3 鬱血性心衰竭 (congestive heart failure, CHF)......................................- 8 - 2.3-4 慢性腎臟疾病 (chronic kidney disease, CKD).......................................- 8 - 2.3-5 愛滋病 (acquired immune deficiency syndrome, AIDS)........................- 9 - 2.3-6 其他.........................................................................................................- 9 - 2.4 惡質症的相關機制.....................................................................................- 9 - 2.5 惡質症所導致的全身性影響..................................................................- 10 - 2.5-1 骨骼肌...................................................................................................- 10 - 2.5-2 脂肪組織...............................................................................................- 11 - 2.5-3 心臟.......................................................................................................- 11 - 2.5-4 血液.......................................................................................................- 12 - 2.5-5 肝臟.......................................................................................................- 12 - 2.5-6 大腦.......................................................................................................- 12- 2.5-7 腸道.......................................................................................................- 12 - 2.5-8 胰腺.......................................................................................................- 13 - 2.5-9 骨骼.......................................................................................................- 13 - 2.5-10 睪丸和卵巢.........................................................................................- 13 - 2.6 惡質症的治療...........................................................................................- 14 - 2.6-1 藥物治療 (pharmacologic treatment) ...................................................- 14 - 2.6-2 營養治療 (nutritional treatment) ..........................................................- 14 - 2.6-3 運動治療 (exercise treatment) .............................................................- 15 - 2.7 胰臟癌與惡質症的關聯性......................................................................- 15 - 第三節 生物標記....................................................................................- 15 - 3.1 生物標記之定義.......................................................................................- 15 - 3.2 胰臟癌之生物標記...................................................................................- 16 - 3.3 惡質症之潛力生物標記...........................................................................- 16 - 3.3-1 介白素-1 (interleukin-1, IL-1) ..............................................................- 17 - 3.3-2 介白素-6 (interleukin-6, IL-6) ..............................................................- 17 - 3.3-3 腫瘤壞死因子-α (tumor necrosis factor-α, TNF-α) .............................- 17 - 3.3-4 瘦素 (Leptin).........................................................................................- 18 - 第四節 S100蛋白...................................................................................- 19 - 4.1 S100A8.....................................................................................................- 19 - 4.2 S100A9.....................................................................................................- 19 - 4.3 S100A8/A9...............................................................................................- 21 - 第五節 研究動機....................................................................................- 22 - 第二章 實驗材料................................................................................- 23 - 第一節 細胞株........................................................................................- 23 - 1.1 老鼠肌肉細胞株.......................................................................................- 23 - 1.2 人類胰腺癌細胞株...................................................................................- 23 - 第二節 臨床檢體....................................................................................- 23 - 第三節 重組蛋白....................................................................................- 23 - 第四節 抗體............................................................................................- 23 - 第五節 藥品............................................................................................- 24 - 第六節 試劑組........................................................................................- 26 - 第七節 儀器............................................................................................- 26 - 第三章 實驗方法................................................................................- 27 - 第一節 生物資訊學分析........................................................................- 27 - 1.1 資料庫選擇 (Selection of database).......................................................- 27 - 1.1-1 美國癌症基因體圖譜計畫TCGA (The Cancer Genome Atlas).........- 27 - 1.1-2 基因型-組織表達資料庫GTEx (Genotype-Tissue Expression).........- 27 - 1.1-3 人類蛋白質地圖HPA (Human Protein Atlas).....................................- 27 - 1.2 篩選工具及分析軟體 (Enrichment analysis).......................................- 28 - 1.2-1 DAVID (Database for Annotation, Visualization and Integrated Discovery).......................................................................................................- 28 - 1.2-2 GO (Gene Ontology) ............................................................................- 28 - 第二節 細胞培養....................................................................................- 28 - 2.1 小鼠肌肉纖維母細胞株 (Mouse myeloblast C2C12 cells)...................- 28 - 2.1-1 小鼠肌肉纖維母細胞繼代培養 (Cell culture of C2C12 cells)............- 28 - 2.1-2 小鼠肌肉纖維母細胞分化 (Myogenic differentiation of C2C12 cells)................................................................................................................- 29 - 2.2 人類胰腺癌細胞株 (Human pancreatic cancer cell line MIA PaCa-2).....................................................................................................................- 29 - 2.2-1 人類胰腺癌細胞繼代培養 (Cell culture of MIA PaCa-2 cells)...........- 29 - 2.2-2 人類胰腺癌細胞培養液的收集 (Collection of MIA PaCa-2 conditioned medium)..........................................................................................................- 29 - 2.3 細胞計數 (Cell counting)....................................................................... - 30 - 第三節 小鼠肌肉細胞形態之觀測........................................................- 30 - 3.1 胰臟癌細胞分泌蛋白刺激小鼠肌肉細胞之型態觀察 (Observation of morphological changes of C2C12 after MIA PaCa-2 conditioned medium treatments).....................................................................................................- 31 - 3.2 候選蛋白刺激小鼠肌肉細胞之型態觀察 (Observation of morphological changes of C2C12 after candidate protein treatments).............................- 31 - 第四節 候選蛋白製備............................................................................- 31 - 4.1 候選蛋白S100A9之表現 (Expression of candidate protein S100A9)..........................................................................................................- 31 - 4.2 候選蛋白S100A9之純化(Purification of candidate protein S100A9)..........................................................................................................- 32 - 第五節 蛋白質分析................................................................................- 32 - 5.1 蛋白質濃度之測定 (BCA protein assay) ..............................................- 32 - 5.1-1 濃度測定原理 (Principle of BCA protein assay) .................................- 32 - 5.1-2 蛋白質濃度測定試劑之成分 (Reagents of BCA protein assay).........- 32 - 5.1-3 蛋白質定量步驟 (Steps of protein quantification)...............................- 32 - 5.2 十二烷基硫酸鈉聚丙烯醯胺膠體電泳 (SDS-PAGE) ..........................- 33 - 5.2-1 膠體電泳原理 (Principle of SDS-PAGE) ............................................- 33 - 5.2-2 膠體製備與架設 (Preparation of SDS-PAGE) ....................................- 33 - 5.2-3 蛋白質樣品緩衝液之配置 (Preparation of protein sample buffer).....- 34 - 5.2-4 蛋白質樣品之處理 (Preparation of protein sample)............................- 34 - 5.2-5 電泳緩衝液之製備 (Preparation of running buffer).............................- 34 - 5.2-6 蛋白質電泳之操作 (SDS-PAGE running)...........................................- 35 - 5.3 膠體之染色 (SDS-PAGE staining) ........................................................- 35 - 5.3-1 CBB染色之原理 (Principle of Coomassie brilliant blue staining)......- 35 - 5.3-2 CBB染色液之製備 (Preparation of CBB dye)....................................- 35 - 5.3-3 CBB退染液之製備 (Preparation of CBB destain buffer)....................- 35 - 5.3-4 CBB染色之步驟 (Steps of CBB staining)...........................................- 35 - 5.4 蛋白質之轉印 (Protein transferring)....................................................- 36 - 5.4-1 蛋白質轉印緩衝液之備製 (Preparation of protein transfer buffer).....- 36 - 5.4-2 蛋白質轉印之步驟 (Steps of protein transferring)...............................- 36 - 5.5 蛋白質轉印膜之染色 (PVDF staining)..................................................- 36 - 5.5-1 Fast green染劑之製備 (Preparation of Fast green dye).......................- 36 - 5.5-2 Fast green染色之步驟 (Steps of Fast green staining)..........................- 36 - 5.6 西方墨點法 (Western blot).....................................................................- 37 - 5.6-1阻攔 (Blocking) ....................................................................................- 37 - 5.6-2 抗體結合 (Antibody hybridization) .....................................................- 37 - 5.6-3 顯影呈像 (Imaging). ............................................................................- 37 - 5.6-4 影像定量 (Quantitative image analysis) ..............................................- 37 - 第六節 臨床檢體之分析........................................................................- 38 - 6.1 酵素免疫分析法 (Enzyme-linked immunosorbent assay, ELISA).....- 38 - 6.1-1 酵素免疫分析法之原理 (Principle of ELISA) ...................................- 38 - 6.1-2 酵素免疫分析法試劑之配製 (Preparation of ELISA buffer)..............- 38 - 6.1-3 酵素免疫分析法之步驟 (Steps of ELISA) .........................................- 38 - 6.2 免疫組織化學染色 (Immunohistochemistry, IHC)..............................- 39 - 6.2-1 免疫組織化學染色之原理 (Principle of IHC).....................................- 39 - 6.2-2 免疫組織化學染色試劑之配製 (Preparation of IHC buffer)..............- 39 - 6.2-3 免疫組織化學染色之步驟 (Steps of IHC)...........................................- 40 - 6.2-4 免疫組織化學染色結果定量分析 (IHC scoring system /H-score).....- 40 - 第四章 實驗結果................................................................................- 42 - 第一節 胰臟癌中致惡質症因子之篩選....................................................- 42 - 1.1 胰臟癌細胞MIA PaCa-2之分泌型蛋白誘發小鼠肌肉纖維母細胞C2C12萎縮................................................................................................................- 42 - 1.2 利用大數據分析方法找出胰臟癌分泌的潛力致惡質症因子..............- 42 - 第二節 潛力胰臟癌致惡質症因子之功能測試.......................................- 43 - 第三節 潛力胰臟癌致惡質症因子之作用機制.......................................- 44 - 第四節 潛力胰臟癌致惡質症因子調控肌肉之作用機制模型............- 45 - 第五節 潛力胰臟癌致惡質症因子作為生物標記之臨床檢體驗證...- 46 - 5.1 TNF-α和IL-6在臨床病人血清的表現、ROC分析與臨床病理特徵的相關性................................................................................................................- 46 - 5.2 S100A8在臨床病人血清的表現、ROC分析以及與臨床病理特徵的相關性................................................................................................................- 47 - 5.3 S100A8在臨床組織切片的表現與分析................................................- 48 - 5.4 S100A9在臨床病人血清的表現、ROC分析以及與臨床病理特徵的相關性................................................................................................................- 48 - 5.5 S100A9在臨床組織切片的表現與分析................................................- 48 - 5.6 S100A8/A9在臨床病人血清的表現、ROC分析與臨床病理特徵的相關性....................................................................................................................- 49 - 5.7 S100A8/A9在臨床組織切片的表現與分析..........................................- 49 - 第六節 潛力胰臟癌致惡質症生物標記ㄉ惡ROC分析.....................- 50 - 第五章 討論........................................................................................- 52 - 第一節 胰臟癌致惡質症的特殊性........................................................- 52 - 1.1 胰臟癌細胞分泌致惡質症因子..............................................................- 52 - 1.2 胰臟癌分泌具發炎特性之潛力致惡質症因子......................................- 52 - 1.3 利用生物資訊學工具找尋胰臟癌致惡質症相關因子..........................- 52 - 第二節 致惡質症因子可使小鼠肌肉細胞C2C12萎縮......................- 54 - 第三節 惡質症的調控機制....................................................................- 55 - 3.1 誘發惡質症的相關機制...........................................................................- 55 - 3.2 惡質症相關因子Atrogin-1與MuRF-1的角色...................................- 56 - 第四節 S100A8、S100A9以及S100A8/A9相關之臨床研究...........- 57 - 4.1 血清樣本...................................................................................................- 57 - 4.2 組織樣本...................................................................................................- 58 - 第五節 複合性生物標記 (multi-biomarker panel) ............................- 59 - 第六節 未來展望....................................................................................- 60 - 第六章 參考文獻................................................................................- 61 - 表..........................................................................................................- 68 - 圖..........................................................................................................- 71 - 附錄 .....................................................................................................- 90 -" | |
| dc.language.iso | zh-TW | |
| dc.subject | 胰臟癌 | zh_TW |
| dc.subject | 惡質症 | zh_TW |
| dc.subject | 生物標記 | zh_TW |
| dc.subject | S100A8 | zh_TW |
| dc.subject | S100A8/A9異二聚體 | zh_TW |
| dc.subject | S100A9 | zh_TW |
| dc.subject | S100A8/A9 heterodimer | en |
| dc.subject | cachexia | en |
| dc.subject | biomarker | en |
| dc.subject | S100A8 | en |
| dc.subject | S100A9 | en |
| dc.subject | pancreatic cancer | en |
| dc.title | 探討S100A8、S100A9、S100A8/A9作為胰臟癌誘發惡質症潛在生物標記的角色及臨床應用 | zh_TW |
| dc.title | "Investigating the Roles and Prospect of S100A8, S100A9, and S100A8/A9 as Potential Biomarkers of Pancreatic Cancer Associated Cachexia" | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 周綠蘋(Lu-Ping Chow) | |
| dc.contributor.oralexamcommittee | 廖偉智(Hsin-Tsai Liu),賴亮全(Chih-Yang Tseng) | |
| dc.subject.keyword | 惡質症,胰臟癌,生物標記,S100A8,S100A9,S100A8/A9異二聚體, | zh_TW |
| dc.subject.keyword | cachexia,pancreatic cancer,biomarker,S100A8,S100A9,S100A8/A9 heterodimer, | en |
| dc.relation.page | 92 | |
| dc.identifier.doi | 10.6342/NTU202104570 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-12-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| dc.date.embargo-lift | 2024-12-31 | - |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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