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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊雅倩(Ya-Chien Yang) | |
| dc.contributor.author | Po-Lin Chen | en |
| dc.contributor.author | 陳柏霖 | zh_TW |
| dc.date.accessioned | 2021-06-17T06:01:26Z | - |
| dc.date.available | 2022-03-05 | |
| dc.date.copyright | 2019-03-05 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-02-11 | |
| dc.identifier.citation | 1 台灣衛生福利部2017公布106年癌症資料.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/71476 | - |
| dc.description.abstract | 大腸直腸癌在世界癌症死亡率排名位於前三名，顯示需要更多研究了解此疾病。先前本實驗室研究於人類第三號染色體3p26.3 鑑定Contactin 4 (CNTN4) 於大腸直腸癌可能扮演抑癌基因的角色。於HCT116細胞表現CNTN4可抑制細胞增生、固著及非固著依賴性胞落形成的能力；在動物實驗則顯示CNTN4可抑制HCT116細胞於裸鼠皮下腫瘤的生成及血管新生。目前對於CNTN4調控的抑癌機轉尚未明確，先前研究指出CNTN4可能透過結合蛋白PTPRG進行訊息調控路徑，因此本論文先利用實驗室收集51對大腸直腸癌檢體檢測PTPRG，結果顯示在大腸直腸癌PTPRG基因表現與配對正常黏膜組織相比無異；同時以免疫共沉澱法證實PTPRG與CNTN4的交互作用。本論文進一步利用人類磷酸化蛋白激酶晶片檢測單一穩定表現CNTN4之HCT116細胞株，探討可能受PTPRG影響的蛋白磷酸化機制，結果顯示HCT116 細胞表現CNTN4後可大幅降低CREB磷酸化；以西方點墨法亦確認CREB及其上游分子Erk1/2，磷酸化程度明顯和CNTN4表現量呈負相關；當以siRNA抑制CNTN4表現，可恢復CREB及Erk1/2之磷酸化。另外，結合TCGA及GSEA進行生物資訊分析，其結果顯示氧化磷酸化(OXPHOS)、三羧酸循環(TCA cycle)及丙酮酸代謝(Pyruvate metabolism)之能量代謝相關路徑與CNTN4表現呈現負相關。為探討CNTN4是否藉由調控能量代謝抑制HCT116細胞生長，以海馬生物能量測定儀檢測細胞能量代謝狀態，結果顯示CNTN4表現於HCT116細胞明顯弱化粒線體功能運作，後續以西方點墨法及即時定量聚合酶連鎖反應確認HCT116 細胞表現CNTN4可明顯降低粒線體生合成相關的重要轉錄因子PGC-1a表現，而以siRNA抑制CNTN4表現則可恢復PGC-1a表現，同時也觀察到PGC-1a調控下游TFAM表現量亦受CNTN4抑制。利用流式細胞儀及即時定量聚合酶連鎖反應確認HCT116 細胞表現CNTN4後大幅降低粒線體質量及粒線體DNA拷貝數，以siRNA抑制CNTN4表現後，則可恢復之。利用螢光染色觀察粒線體形態變化，當HCT116 細胞表現CNTN4可出現似粒線體分裂聚集現象。綜合以上，我們先確認CNTN4表現能抑制HCT116細胞的CREB及其上游Erk1/2之磷酸化，並且藉由生物資訊分析假設能量代謝可能為CNTN4影響的重要路徑；再以海馬生物能量測定結果支持表現CNTN4可弱化粒線體功能，而其可能是透過抑制CREB磷酸化而減少下游PGC-1a表現，進而影響粒線體生合成及降低粒線體DNA拷貝數之機制。 | zh_TW |
| dc.description.abstract | Colorectal cancer (CRC) is one of the top three leading causes of cancer death in the world. Although the annual incidence due to timely screening has been decreased in these years, its annual mortality keeps the highest among human cancers indicating it still needs more study. Previously, we have identified Contactin 4 (CNTN4) as a novel tumor suppressor gene located at chromosome 3p26.3, which is lost in CRC tumors at a high frequency. Ectopic expression of CNTN4 in HCT116 cells could reduce cell proliferation, anchorage-dependent and anchorage-independent colony formation in vitro. Furthermore, CNTN4 expression could inhibit the tumorigenesis of subcutaneous xenograft and tumor angiogenesis in nude mice. However, the mechanism of CNTN4 is still not clear. It showed CNTN4 might interact with PTPRG to modulate cell signaling pathway. Therefore, we detected and observed the PTPRG gene expression upregulation in 51 pair CRC primary tumor when compaired with normal mucosa. We also confirmed the interaction between CNTN4 and PTPRG by co-immunoprecipitation. In the study, by Human Phospho-Kinase Array, we found ectopic expression of CNTN4 in HCT116 cells could obviously reduce CREB phosphorylation compared with HCT116/Mock and the downregulation of phospho-CREB as well as its upstream regulation, phospho-Erk1/2 was further observed by Western Blot. Additionally, by knockdown of CNTN4 expression with siRNA, the phosphorylation of CREB and ERK1/2 could be restored. On the other hand, we utilized thecolorectal adenocarcinoma dataset of TCGA and GSEA software to perform bioinformatic analysis, and the result showed that CNTN4 expression is nagtively correlated with energy metabolism pathway, including OXPHOS, TCA cycle and pyruvate metabolism. To investigate whether CNTN4 inhibits HCT116 cell proliferation through modulating metabolic activity, we detected energy metabolic status of HCT116 cells expressing CNTN4 by Seahorse analysis. The result showed ectopic expression of CNTN4 decreased mitochondrial function. In addition, we found CNTN4 expression in HCT116 cells reduced PGC-1a expression, an important transcription factor affecting the synthesis of mitochondria, and the phenomen could be restored by CNTN4 knockdown with siRNA. Futhermore, TFAM, a target gene of PGC-1a, were also reduced by CNTN4 expression. Finally, we found ectopic expression of CNTN4 in HCT116 cells reduced mitochondrial mass and mitochondrial DNA. In the cells, the mitochondrial morphology became punctated cluster, which is associated with mitochondrial fission. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T06:01:26Z (GMT). No. of bitstreams: 1 ntu-108-R05424023-1.pdf: 5042140 bytes, checksum: 36ad7e5a066f03590883331ef95077bd (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 致謝 i
摘要 ii Abstract iv 縮寫對照表 vi 圖目錄 xiv 表目錄 xv 一、緒論 1 1. 大腸直腸癌 1 1.1 簡介 1 1.2生成機制 2 1.2.1 染色體的不穩定性 (Chromosomal instability, CIN) 2 1.2.2 微衛星不穩定性 (Microsatellite instability, MSI) 2 1.2.3 表觀基因變異(epigenetic alterations) 2 1.3 大腸直腸癌分子特徵與標靶藥物的綜合分類系統 3 1.4 癌症分期 4 1.4.1 Dukes分期系統 4 1.4.2 TNM分期系統 5 1.4.3 AJCC/UICC分期系統 6 2. Contactin 4 (CNTN4) 7 2.1 Contactin家族與CNTN4簡介 7 2.2 CNTN4相關研究 8 2.3 CNTN4與癌症相關研究 8 3. Protein Tyrosine Phosphatase Receptor gamma (PTPRG) 10 3.1 PTPRG簡介 10 3.2 PTPRG與CNTN4相關研究 10 4. 細胞能量代謝 12 4.1 糖解作用 Glycolysis 12 4.2 丙酮酸脫羧反應 Pyruvate oxidative decarboxylation 12 4.3 三羧酸循環 TCA cycle 13 4.4 電子傳遞鏈 Electron Transport Chain 13 4.5 癌症細胞能量代謝變化 13 4.5.1 Warburg effect 13 4.5.2 粒線體能量代謝 14 5. 粒線體動態平衡 16 5.1 融合Fusion 16 5.1.1 外膜融合 16 5.1.2 內膜融合 16 5.2 分裂Fission 17 5.2.1 外膜分裂 17 5.2.2 內膜分裂 17 5.3 粒線體生合成 Mitochondrial biogenesis 18 6. 實驗室先前CNTN4相關研究 19 6.1 第三號染色體失異合性檢測 19 6.2 CNTN4抑癌功能之確認 19 6.3 CNTN4抑制大腸直腸癌細胞表現促血管新生因子 urokinase-type plasminogen activator (uPA) 之確認 19 6.4 溶解型CNTN4抑癌功能之確認 20 二、研究目標 21 三、材料與方法 22 1. 細胞培養 22 2. 利用siRNA抑制CNTN4表現 23 3. 蛋白質的抽取及定量 23 4. 西方墨點法 24 5. DNA 萃取 25 6. RNA 萃取 26 7. 反轉錄合成互補 DNA 26 8. 免疫共沉澱法 27 9. 即時定量聚合酶連鎖反應 27 10. 海馬生物能量測定儀 28 11. 粒線體形態與總量分析 30 12. 人類磷酸化蛋白激酶晶片檢測 31 13. 公開資料庫之數據分析 31 14. 統計 31 四、研究結果 32 1. 探討PTPRG基因於大腸直腸癌病患腫瘤之表現 32 2. 利用免疫共沉澱法驗證CNTN4與PTPRG的蛋白質交互作用 32 3. 利用磷酸化蛋白激酶晶片檢測於HCT116細胞表現CNTN4之影響 33 4. 探討於HCT116表現CNTN4對於磷酸化蛋白激酶之調控 33 5. 探討HCT116表現CNTN4對於CREB其上游路徑之調控 34 6. 利用TCGA及GSEA 軟體分析CNTN4與生化途徑相關性 34 7. 利用海馬生物能量測定儀檢測於HCT116細胞表現CNTN4可抑制粒線體能量代謝活性 35 8. 利用TCGA分析大腸直腸癌腫瘤之CNTN4和能量代謝途徑基因之相關性 36 9. 探討於HCT116表現CNTN4細胞對於能量代謝途徑的基因變化 36 10. 探討於HCT116表現CNTN4細胞對CREB調控PGC-1及其下游TFAM變化 37 11. 利用粒線體螢光染色探討CNTN4表現造成HCT116細胞粒線體基因減少 38 12. 利用粒線體螢光染色探討CNTN4表現造成HCT116細胞粒線體質量減少 38 13. 利用粒線體螢光染色探討CNTN4表現造成HCT116細胞粒線體形態改變 39 五、討論 40 圖 46 表 75 參考資料 86 | |
| dc.language.iso | zh-TW | |
| dc.subject | 粒線體 | zh_TW |
| dc.subject | 能量代謝 | zh_TW |
| dc.subject | CREB磷酸化 | zh_TW |
| dc.subject | Contactin 4 | zh_TW |
| dc.subject | 大腸直腸癌 | zh_TW |
| dc.subject | mitochondria | en |
| dc.subject | energy metabolism | en |
| dc.subject | colorectal cancer | en |
| dc.subject | CREB phosphorylation | en |
| dc.subject | Contactin 4 | en |
| dc.title | 探討Contactin 4於大腸直腸癌對細胞能量代謝的影響 | zh_TW |
| dc.title | Study of Contactin 4 – mediated changes in cellular energy metabolism in colorectal cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 蘇剛毅(Kang-Yi Su),郭靜穎(Ching-Ying Kuo),潘思樺(Szu-Hua Pan),張育嘉(Yu-Jia Chang) | |
| dc.subject.keyword | 大腸直腸癌,Contactin 4,CREB磷酸化,能量代謝,粒線體, | zh_TW |
| dc.subject.keyword | colorectal cancer,Contactin 4,CREB phosphorylation,energy metabolism,mitochondria, | en |
| dc.relation.page | 94 | |
| dc.identifier.doi | 10.6342/NTU201900417 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-02-11 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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