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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99947完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 周綠蘋 | zh_TW |
| dc.contributor.advisor | Lu-Ping Chow | en |
| dc.contributor.author | 施佩吟 | zh_TW |
| dc.contributor.author | Pei-Yin Shih | en |
| dc.date.accessioned | 2025-09-22T16:06:12Z | - |
| dc.date.available | 2025-09-23 | - |
| dc.date.copyright | 2025-09-22 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-08-01 | - |
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Ludwig, et al., C/EBPdelta-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9. Elife, 2022. 11. Hao, S., Z. Yao, and Y. Liu, LINC00847 drives pancreatic cancer progression by targeting the miR-455-3p/HDAC4 axis. Arch Med Sci, 2024. 20(3): p. 847–862. Yang, J., C. Chheda, A. Lim, et al., HDAC4 Mediates Smoking-Induced Pancreatic Cancer Metastasis. Pancreas, 2022. 51(2): p. 190–195. Geng, H., C.T. Harvey, J. Pittsenbarger, et al., HDAC4 protein regulates HIF1alpha protein lysine acetylation and cancer cell response to hypoxia. J Biol Chem, 2011. 286(44): p. 38095–38102. Fan, R., H. Satilmis, N. Vandewalle, et al., Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma. J Immunother Cancer, 2023. 11(1). Rodriguez-Manzaneque, J.C., T.F. Lane, M.A. Ortega, et al., Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A, 2001. 98(22): p. 12485–90. Olsson, A., J. Nakhle, A. Sundstedt, et al., Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment. J Immunother Cancer, 2015. 3: p. 53. Yuan, Y., G. Hilliard, T. Ferguson, et al., Cobalt inhibits the interaction between hypoxia-inducible factor-alpha and von Hippel-Lindau protein by direct binding to hypoxia-inducible factor-alpha. J Biol Chem, 2003. 278(18): p. 15911–6. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99947 | - |
| dc.description.abstract | 胰臟癌是一種高度致死率的腫瘤，其臨床特徵包括進展迅速、診斷困難以及預後不良。由於約 80-90% 的患者在疾病晚期才被確診，錯失手術治療的時機，導致五年內生存率普遍低於 10%。研究顯示，約有半數胰臟癌患者在確診前一年內出現新生糖尿病，而此類患者於後續一至三年間罹患胰臟癌的風險顯著升高，顯示與胰臟惡性腫瘤相關的新生糖尿病 (PCDM) 可能為胰臟癌的潛在早期徵兆。本實驗室先前研究發現， PCDM 患者的腫瘤組織中，具有高度表現的 S100A9，此分子會導致骨骼肌產生胰島素阻抗，並降低胰島 β 細胞的胰島素生成能力。然而， S100A9 在胰臟癌細胞中表現上升的機制，及其對胰臟癌惡性行為的影響仍有待釐清。
本研究建立了 S100A9 過表現之胰臟癌細胞株 MIA PaCa-2，結果顯示 S100A9 可促進癌細胞之增生、遷移與侵襲能力;此外，我們發現 S100A9 表現會在缺氧環境中進一步上升。 Tasquinimod 作為一種 HDAC4 抑制劑，在缺氧條件下能減少 HDAC4、 HDAC3 與 HIF-1α 之間的交互作用，同時抑制 HIF-1α 表現，進而降低 S100A9 蛋白表現。進一步在臨床檢體中驗證， PCDM 患者腫瘤組織中的 S100A9 與 HIF-1α 表現皆明顯高於非糖尿病胰臟癌 (PC) 患者。 綜合上述結果， S100A9 在胰臟癌增生與轉移，以及在 PCDM 形成中具有關鍵調控角色，極具潛力作為胰臟癌早期生物標誌; Tasquinimod 具備同時抑制胰臟癌進展及緩解糖尿病相關症狀的潛力，未來可望作為治療 PCDM 的創新治療策略。 | zh_TW |
| dc.description.abstract | Pancreatic cancer is a highly lethal malignancy, characterized by its insidious onset and the limited sensitivity of current diagnostic tools. As a result, approximately 80–90% of patients are diagnosed at an advanced stage, making them ineligible for surgical resection and contributing to a poor overall long-term survival rate of only 1–5%. Previous studies have shown that around 50% of pancreatic cancer patients develop new- onset diabetes approximately one year before diagnosis. Moreover, individuals with new- onset diabetes have a 5- to 8-fold increased risk of being diagnosed with pancreatic cancer within the subsequent 1 to 3 years. These findings suggest that pancreatic cancer-induced diabetes (PCDM) may serve as a potential early indicator of the disease. Our previous study demonstrated that tumor tissues from PCDM exhibit markedly elevated levels of S100A9, a diabetogenic factor that induces insulin resistance in skeletal muscle and impairing insulin production in pancreatic β cells. However, the molecular mechanisms driving S100A9 upregulation in pancreatic cancer cells and its role in tumor progression remain unclear.
In this study, we established a S100A9-overexpressing pancreatic cancer cell line (MIA PaCa-2) and found that S100A9 promotes cancer cell proliferation, migration, and invasion. Furthermore, S100A9 expression was found to be further increased under hypoxic conditions. Tasquinimod, an HDAC4 inhibitor, was shown to disrupt the interaction among HDAC4, HDAC3, and HIF-1α under hypoxia, thereby downregulating both HIF-1α and S100A9 expression. Immunohistochemical staining of clinical specimens confirmed that S100A9 and HIF-1α levels were significantly elevated in tumor tissues from PCDM patients compared to those from non-diabetic pancreatic cancer (PC) patients. Taken together, these findings demonstrate that S100A9 plays a pivotal role in promoting pancreatic cancer cell proliferation and metastasis, and the pathogenesis of PCDM. S100A9 may serve as a promising early biomarker for pancreatic cancer. In addition, Tasquinimod shows potential as a novel therapeutic strategy capable of both inhibiting pancreatic cancer progression and alleviating diabetes-associated symptoms in PCDM patients. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-22T16:06:12Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-22T16:06:12Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
謝誌 ii 中文摘要 iii 英文摘要 iv 縮寫 vi 目次 viii 圖次 xiii 附錄 xiv 第一章 導論 1 1.1 胰臟癌 （Pancreatic cancer） 1 1.1.1 胰臟癌之流行病學 1 1.1.2 胰臟癌種類 1 1.1.3 胰臟惡性腫瘤之潛在危險因素 2 1.1.4 治療方式 5 1.1.5 胰臟癌的初期診斷與臨床挑戰 8 1.2 胰臟癌相關之新發糖尿病 （Pancreatic cancer-associated diabetes, PCDM）11 1.2.1 疾病介紹 11 1.2.2 疾病機轉 12 1.2.3 疾病特性 13 1.3 S100A9蛋白功能與特性 16 1.3.1 S100 蛋白家族的種類與特性 16 1.3.2 S100A9 的生理功能 17 1.3.3 S100A9 在癌症中的角色 18 1.4 缺氧 （Hypoxia） 20 1.4.1 缺氧的定義及相關機轉 20 1.4.2 缺氧誘導因子 （Hypoxia-inducible factor 1-alpha, HIF-1α） 21 1.4.3 缺氧對胰臟癌的影響 22 1.5 Tasquinimod 23 1.5.1 Tasquinimod 介紹以及抗腫瘤效果 23 1.5.2 Tasquinimod 的作用機制 23 1.6 研究動機 25 第二章 實驗材料 26 2.1 胰臟癌細胞株 26 2.2 胰臟癌組織切片 26 2.2.1 患者資訊 26 2.3 儀器與裝置 26 2.4 細胞培養耗材 27 2.5 抗體 28 2.6 試劑與藥品 29 2.7 數據分析軟體與生物資料庫 34 第三章 實驗方法 35 3.1 細胞培養 35 3.1.1 細胞繼代 35 3.1.2 細胞計數 35 3.1.3 細胞冷凍 35 3.2 建立過表現S100A9的細胞株 36 3.2.1 質體建構與純化 36 3.2.2 質體轉染細胞 （Transform） 37 3.3 細胞內分子機制分析 38 3.3.1 缺氧條件誘發 38 3.3.2 抑制劑處理 38 3.4 西方墨點法 （Western Blot） 40 3.4.1 細胞蛋白萃取 40 3.4.2 蛋白質定量 40 3.4.3 電泳 （SDS-PAGE） 40 3.4.4 蛋白轉漬 （Western Blot Transfer） 41 3.4.5 蛋白質免疫分析 （Immunoblotting analysis） 41 3.5 免疫共沉澱 （Co-Immunoprecipitation） 42 3.6 免疫螢光染色 （Immunofluorescence Staining） 43 3.6.1 細胞培養 43 3.6.2 抗體偵測蛋白 43 3.6.3 影像分析 43 3.7 細胞活性測定 （Cell viability assay） 44 3.7.1 藥物毒性分析 44 3.7.2 細胞增生能力分析 44 3.8 細胞遷移能力分析 （Would healing assay） 45 3.9 細胞侵襲實驗 （Transwell invasion assay） 45 3.10 組織免疫染色 （Immunohistochemistry staining analysis） 46 3.11 生物資訊學分析 47 第四章 實驗分析結果 48 4.1 S100A9 在胰臟癌中的功能角色與其上游調控路徑 48 4.1.1 S100A9 可增強胰臟癌細胞之增生、遷移與侵襲能力 48 4.1.2 HIF-1α 可能參與調控胰臟癌中 S100A9 的表現 49 4.1.3 TLR4 受體參與調控胰臟癌中 S100A9 的表現 49 4.2 Tasquinimod 在胰臟癌細胞中的藥理作用與相關機制 50 4.2.1 Tasquinimod 可於缺氧環境下抑制胰臟癌細胞生長並下調 S100A9 蛋白表現 50 4.2.2 Tasquinimod 干擾 HIF-1α、HDAC4 與 HDAC3 之間的交互作用 51 4.3 PC與PCDM患者胰臟組織中的缺氧情況 52 4.3.1 PCDM患者胰臟組織中HIF-1α與S100A9表現上升 52 第五章 討論 53 5.1 S100A9 對胰臟癌的影響 53 5.1.1 探討 S100A9 在腫瘤細胞生長與擴散能力中的功能角色 53 5.1.2 S100A9 參與胰臟癌進展的潛在分子機制 53 5.2 缺氧與胰臟惡性腫瘤引發之新生糖尿病（PCDM）的關聯性 54 5.2.1 HIF-1α在胰臟癌相關糖尿病（PCDM）的表現 54 5.2.2 HIF-1α 與調控 S100A9 上調之因子 55 5.2.3 S100A9 受體與 HIF-1α、S100A9 表現上調之關係 56 5.3 探討 Tasquinimod 對胰臟癌相關糖尿病的影響 57 5.3.1 Tasquinimod 對胰臟癌細胞之抑制效果與潛在機轉 57 5.3.2 Tasquinimod 調控 HIF-1α 表現的可能機制 57 5.3.3 Tasquinimod 抑制胰臟癌中 S100A9 表現的相關機制 58 5.4 結論與展望 60 第六章 參考文獻 61 圖表 72 附錄圖表 85 | - |
| dc.language.iso | zh_TW | - |
| dc.subject | 胰臟癌誘導之新生糖尿病 | zh_TW |
| dc.subject | 缺氧誘導因子 | zh_TW |
| dc.subject | 胰臟癌 | zh_TW |
| dc.subject | 胰島 β 細胞功能障礙 | zh_TW |
| dc.subject | 胰島素阻抗 | zh_TW |
| dc.subject | S100A9 | zh_TW |
| dc.subject | Pancreatic cancer | en |
| dc.subject | β cell dysfunction | en |
| dc.subject | insulin resistance | en |
| dc.subject | HIF-1α | en |
| dc.subject | S100A9 | en |
| dc.subject | Pancreatic cancer-associated diabetes | en |
| dc.title | 探討胰臟癌誘導糖尿病中 HIF-1α介導的S100A9表現機轉以及功能 | zh_TW |
| dc.title | Investigating the HIF-1α-Mediated Signaling Pathway and the Function of S100A9 in Pancreatic Cancer-Associated Diabetes | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.coadvisor | 李明學 | zh_TW |
| dc.contributor.coadvisor | Ming-Shyue Lee | en |
| dc.contributor.oralexamcommittee | 潘思樺;黃楓婷 | zh_TW |
| dc.contributor.oralexamcommittee | Szu-Hua Pan;Feng-Ting Huang | en |
| dc.subject.keyword | 胰臟癌,胰臟癌誘導之新生糖尿病,胰島素阻抗,胰島 β 細胞功能障礙,S100A9,缺氧誘導因子, | zh_TW |
| dc.subject.keyword | Pancreatic cancer,Pancreatic cancer-associated diabetes,insulin resistance,β cell dysfunction,S100A9,HIF-1α, | en |
| dc.relation.page | 98 | - |
| dc.identifier.doi | 10.6342/NTU202503118 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-08-01 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | - |
| dc.date.embargo-lift | 2030-07-31 | - |
| 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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