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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 周綠蘋(Lu-Ping Chow) | |
dc.contributor.author | Peng-Ruei Chen | en |
dc.contributor.author | 陳芃瑞 | zh_TW |
dc.date.accessioned | 2021-06-17T06:02:58Z | - |
dc.date.available | 2024-03-05 | |
dc.date.copyright | 2019-03-05 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-01-28 | |
dc.identifier.citation | 1. World Cancer Research Fund Cancer Statistics. 2016; Available from: http://www.wcrf.org/cancer_statistics/world_cancer_statistics.php.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71547 | - |
dc.description.abstract | 胰臟癌是目前全球癌症致死率排名中的第三位,在常見的癌症中,胰臟癌擁有最低的5年存活率。85%的病患被診斷出胰臟癌時已至晚期,因其缺乏早期診斷的方法。過去的研究指出,大約40%的胰臟癌患者在被診斷出胰臟癌的前兩年內會發生糖尿病,此種胰臟癌誘發之糖尿病是一個早期發現胰臟癌的機會。鑑於胰臟癌誘發之糖尿病是由腫瘤分泌的致糖尿病因子所導致,鑑定該致糖尿病因子為何,能夠幫助我們了解致病的機制,及提供區分胰臟癌誘發之糖尿病與第二型糖尿病的生物標記。
在實驗室先前的研究中,我們收集了胰臟癌細胞株的分泌性蛋白,並透過蛋白質體學、DNA微陣列及生物資訊分析結果,鑑定出S100A9作為致糖尿病因子的候選蛋白。並且於後續的實驗,發現S100A9能抑制肌肉細胞攝取葡萄糖的能力,並且觀察到S100A9高表現於胰臟癌組織及周圍基質的現象,說明S100A9可能在新生糖尿病的形成中扮演角色。 在本篇中,我們為了評估S100A9作為生物標記的能力,我們收集了臨床上六組病患的血清檢體,分別為健康人、第二型糖尿病、胰臟癌新生糖尿病、無糖尿病之胰臟癌、胰臟炎,及其他胰臟腫瘤族群。我們發現血清SX A9濃度於胰臟癌新生糖尿病患者相較於其它族群顯著提高,並且經ROC分析得到S100A9能夠區分胰臟癌新生糖尿病及第二型糖尿病的結果。我們進一步探討生物標記的分析,發現合併S100A9及CA19-9兩種血液生物標記,得到比兩者單獨使用更佳的區分效果。 此外,我們也探討了致糖尿病因子S100A9於新生糖尿病中扮演的角色。結果顯示S100A9能夠藉由與TLR4交互作用造成胰島素阻抗。TLR4下游的IKKβ因Ser181磷酸化而活化,進而將IRS-1的抑制型Ser307位點磷酸化,造成IRS-1活性下降,導致下游Akt的磷酸化被抑制,胰島素訊息傳遞被阻礙。 總結本篇研究,我們證實S100A9可作為診斷PCDM的潛力生物標記,並且合併S100A9與CA19-9可以在胰臟癌的早期偵測達到更佳的效果。此外,我們也證明S100A9會藉由與TLR4的交互作用造成胰島素阻抗。我們的實驗成果可幫助我們釐清胰臟癌導致新生糖尿病的機制,以及提供一個新的胰臟癌早期偵測研究方向。 | zh_TW |
dc.description.abstract | Pancreatic cancer (PC) is the third leading cause of cancer-related deaths in the world with the lowest 5-year survival among major cancers. 85% of patients are diagnosed at advanced stage owing to the lack of early-stage detection methods. Previous studies demonstrated that approximately 40% patients of PC develop pancreatic cancer-associated diabetes mellitus (PCDM) within 2 years preceding the diagnosis of PC, providing a window of opportunity for early detection. Given that PCDM is mediated by unknown tumor-secreted diabetogenic factors, identifying the diabetogenic factors may help understand its pathogenesis and discover novel biomarkers to discriminate PCDM from type 2 diabetes mellitus (T2DM).
In our previous studies, we identified S100A9 as a candidate diabetogenic factor in condition media (CM) of two pancreatic cancer cell lines (MiaPaCa-2 and PANC-1) by LC-MS/MS combining DNA microarray. We produced S100A9 recombinant protein and discovered that S100A9 can reduce glucose uptake in C2C12 cells. Besides, we also found that S100A9 is highly expressed both in cancer cells and tumor stroma of PCDM. The results revealed that S100A9 played an important role in PCDM. To evaluate the usefulness of S100A9 as a diagnostic biomarker, we collected different groups of patients’ samples, including normal healthy control, type 2 diabetes mellitus (T2DM), PC without DM, PCDM, pancreatitis, and other pancreatic tumors. We found that serum S100A9 concentration was higher in PCDM than in other groups and could distinguish PCDM from T2DM. Furthermore, the combination of S100A9 and CA19-9 constituted a more discriminatory panel than either marker alone. In addition, we investigated the role of diabetogenic factor S100A9 in PCDM. Our results showed that S100A9 caused insulin resistance through interacting with Toll-like receptor 4 (TLR4), which activates IκB kinase-β (IKK-β) by Ser181 phosphorylation. The phosphorylated IKK-β then stimulates inhibitory Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1) and therefore suppresses activating Ser 473 phosphorylation of Akt and downstream insulin signaling. In conclusion, we verified S100A9 was a potential diagnostic biomarker for PCDM, and the combination of S100A9 and CA19-9 may facilitate early detection of PC. Moreover, we demonstrated that S100A9 caused insulin resistance through interacting with TLR4. Our results can help us not only for clarifying the pathogenesis of PCDM, but also for early detection of pancreatic cancer. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T06:02:58Z (GMT). No. of bitstreams: 1 ntu-108-R05442025-1.pdf: 4012768 bytes, checksum: 6b85b2d88c954b884fcb5d932bb2c3f6 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口委審定書 1
謝誌 2 中文摘要 3 Abstract 5 縮寫 7 目錄 9 表目錄 13 圖目錄 13 附錄目錄 14 第一章 導論 15 第一節 胰臟癌之概論 15 1.1 胰臟癌之流行病學 15 1.2 胰臟癌之種類 15 1.3 胰臟癌之病徵 16 1.4 胰臟癌之風險因子 16 1.5 胰臟癌之癌前病變與分期 18 1.6 胰臟癌之檢查與診斷 19 1.7 胰臟癌之治療 20 1.8 胰臟癌與糖尿病之關係 20 第二節 新生糖尿病(New-onset diabetes mellitus)之概論 22 2.1 新生糖尿病之定義 22 2.2 新生糖尿病之發現及證據 22 2.3 新生糖尿病之機制 22 2.4 新生糖尿病於胰臟癌篩選之應用潛力 23 第三節 生物標記 24 3.1 生物標記之定義 24 3.2 腫瘤生物標記 24 3.3 生物標記資料分析 25 3.4 胰臟癌之生物標記 26 3.5 早期診斷胰臟癌之難處 27 第四節 胰島素阻抗及胰島素分泌之調控 28 4.1 胰島素受體 (Insulin receptor, IR) 訊息傳遞路徑 28 4.2 胰島素阻抗 29 4.3 胰島素的分泌調控 30 第五節 S100 calcium binding protein A9 (S100A9) 蛋白之功能與調控 30 5.1 S100 protein family 之種類與功能 30 5.2 S100A9 之正常生理功能 31 5.3 S100A9 與胰臟癌之關聯 32 5.4 S100A9 與糖尿病之關聯 32 第六節 研究動機 33 第二章 實驗材料 34 第一節 細胞株 34 第二節 血清樣本 34 第三節 抗體 34 第四節 藥品 35 第五節 試劑組 37 第六節 儀器 38 第三章 實驗方法 39 第一節 細胞培養 (Cell culture) 39 1.1 小鼠肌肉細胞 (C2C12 myoblast cell) 39 1.2 大鼠胰島素瘤細胞 (RIN-m5F insulinoma cell) 39 1.3 大鼠胰島素瘤細胞 (INS-1 insulinoma cell) 40 1.4 細胞計數及細胞存活率(Cell counting and cell viability) 40 第二節 候選蛋白的製備 (Candidate protein preparation) 40 2.1 候選蛋白之質體建構 (Construct of candidate protein) 40 2.2 候選蛋白之表現 (Expression of candidate protein) 41 2.3 候選蛋白之純化 (Purification of candidate protein) 42 第三節 蛋白質之分析 (Protein Analysis) 42 3.1 蛋白濃度之測定 (BCA protein assay) 42 3.2 十二烷基硫酸鈉聚丙烯醯胺膠體電泳 (SDS-PAGE) 43 3.3 膠體之染色 (Protein staining) 45 3.4 蛋白質之轉印 (Protein transferring) 46 3.5 蛋白質轉印膜之染色 46 3.6 西方墨點法 (Western Blot) 47 3.7 共免疫沉澱 (Co-Immunoprecipitation) 47 第四節 臨床檢體之分析 48 5.1 酵素免疫分析法 (Enzyme-linked immunosorbent assay, ELISA) 48 第五節 胞內鈣離子濃度測定 49 5.1 胞內鈣離子濃度測定之原理 49 5.2 試劑及緩衝溶液 49 5.3 測定步驟 50 第六節 基因表現之分析 51 6.1 RNA萃取(RNA extraction) 51 6.2 逆轉錄聚合酶鏈式反應(Reverse transcription) 51 6.3 即時聚合酶鏈式反應(Real-time PCR) 52 第四章 實驗結果 53 第一節 胰臟癌中致糖尿病因子之挑選 53 第二節 臨床檢體之驗證 53 2.1 致糖尿病因子S100A9在臨床病人血清的表現及ROC分析 53 2.2 S100A9於其他良性胰臟疾病之比較 54 2.3 S100A9作為IPMN生物標記之潛力 54 第三節 致糖尿病因子S100A9造成胰島素阻抗之機制 55 第四節 S100A9抑制β細胞葡萄糖誘導胰島素分泌之可能機制探討 56 4.1 S100A9對電壓依賴性鈣離子通道(VDCC)之影響 56 4.2 S100A9對JNK發炎訊息傳遞路徑之影響 57 4.3 S100A9對β細胞內質網壓力(ER stress)之影響 57 第五章 討論 58 第一節 S100 calcium binding protein A9 (S100A9) 蛋白之功能與調控 58 1.1 S100A9之生理功能及參與之訊息傳遞路徑 58 1.2 S100A9於其他癌症扮演之角色 59 第二節 糖尿病中致糖尿病因子之調控 59 第三節 胰臟癌之潛力生物標記蛋白 60 3.1 篩選胰臟癌病患之策略 60 3.2 找尋胰臟癌生物標記之方法學 61 3.3 複合性生物標記(Multiple biomarker)之應用 61 3.4 其他胰臟癌生物標記與比較 62 3.5 IPMN (Intraductal papillary mucinous neoplasms)之生物標記 63 第四節 胰島素阻抗之機制 63 4.1 胰島素受體 (Insulin receptor, IR) 訊息傳遞之負調控者 63 4.2 胰島素訊息傳遞路徑之負回饋調控 64 第五節 其他胰島素分泌減少之機制 65 5.1 JNK、NF-κB pathway 65 5.2 內質網壓力ER stress 66 5.3 PDX-1基因表現 66 第六章 參考文獻 67 表 75 圖 78 附錄 89 | |
dc.language.iso | zh-TW | |
dc.title | 探討致糖尿病因子S100A9於胰臟癌誘發糖尿病之角色及臨床應用 | zh_TW |
dc.title | To Investigate The Role of Diabetogenic Factor S100A9 in Pancreatic Cancer-Associated Diabetes Mellitus and Its Clinical Application | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 龔秀妮,吳明賢,廖偉智 | |
dc.subject.keyword | 胰臟癌,新生糖尿病,胰島素阻抗,生物標記,S100A9, | zh_TW |
dc.subject.keyword | Pancreatic cancer,diabetes,insulin resistance,biomarker,S100A9, | en |
dc.relation.page | 95 | |
dc.identifier.doi | 10.6342/NTU201900222 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-01-29 | |
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 |
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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