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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 胡孟君(Meng-Chun Hu) | |
dc.contributor.author | Pei-Yu Hung | en |
dc.contributor.author | 洪珮瑜 | zh_TW |
dc.date.accessioned | 2021-06-08T02:49:34Z | - |
dc.date.copyright | 2017-09-08 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-17 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20463 | - |
dc.description.abstract | 腎上腺、性腺及胎盤為主要分泌類固醇荷爾蒙的腺體;然而,其他組織如腸道也能自行產生局部糖類皮質素,調控腸道的免疫系統。3β-hydroxysteroid dehydrogenase/△5-△4 isomerase (3β-HSD) 是HSD3B基因的產物,為類固醇荷爾蒙生成重要的酵素。人類具有兩種HSD3B,HSD3B1主要表現在胎盤、周邊組織與腫瘤細胞;HSD3B2則表現在腎上腺與性腺。先前研究指出interleukin-4 (IL-4) 能促進人類大腸癌、乳癌、前列腺等細胞中HSD3B1的表現,但其詳細的調控機制與功能尚不清楚。我們於大腸癌細胞HT-29發現,IL-4能誘導HSD3B1的mRNA與蛋白質量增加。為了瞭解有哪些訊息調控因子參與IL-4誘導HSD3B1表現的過程,我們給予不同激酶抑制劑處理HT-29。Real-time RT-PCR結果顯示,GSK3抑制劑CHIR99021會抑制IL-4誘導HSD3B1表現;當給予IL-4不同的時間處理後,發現CHIR99021於後期 (10-24小時) 才能明顯地降低HSD3B1的表現。已知GSK3活性受PI3K/Akt訊息傳遞路徑所調控,西方墨點法分析結果顯示IL-4能快速但短暫的增加Akt-Ser473 (活化態) 及GSK3β-Ser9 (非活化態) 的磷酸化。若給予PI3K抑制劑LY294002預處理,於早期 (4小時) 即能明顯降低IL-4所誘導的HSD3B1表現,之後HSD3B1的表現反而增加。這些結果說明IL-4會活化PI3K/Akt路徑,引發HSD3B1表現;後期Akt活性減弱,導致GSK3活化,得以再促進HSD3B1表現。此外,我們發現給予IKK抑制劑BMS345541,在IL-4作用的24小時期間幾乎完全抑制HSD3B1 mRNA的產生。已知IKK會活化NF-κB調控下游基因的表現,當給予NF-κB抑制劑Bay117082,會減少50% HSD3B1 mRNA。但檢測NF-κB活化路徑,並未觀察到IL-4對於IκB降解、NF-κB-p65入核及NF-κB-p100/p52有明顯的影響。IL-4除了大幅誘導HSD3B1表現之外,亦會增加糖類皮質素生成相關基因的表現,取HT-29細胞培養液進行糖類皮質素活性分析發現,IL-4會促進HT-29細胞分泌具生物活性的糖類皮質素。綜合結果顯示,在HT-29大腸癌細胞中,IL-4會透過IKK與PI3K/Akt/GSK3訊息傳遞路徑調控HSD3B1的表現,並且促進糖類皮質素的產生。 | zh_TW |
dc.description.abstract | The adrenal glands, gonads and placenta are the major source of steroid hormones;however, extra-glands such as intestine also secrete glucocorticoid (GC) to modulate intestinal immunity. 3β-hydroxysteroid dehydrogenase (3β-HSD), encoded by HSD3B gene, is essential for the production of all classes of steroid hormones. Human have two HSD3B genes, HSD3B1 is the major type of placenta, peripheral tissues and tumors, and HSD3B2 is the major type of adrenal gland and gonads. Previous studies indicated that interleukin-4 (IL-4) induced HSD3B1 expression in human colon, breast cancer cells and normal prostate epithelial cell. However, the mechanisms underlying the IL-4-mediated regulation of HSD3B1 expression remain elusive. Here, we showed that IL-4 greatly enhanced the levels of HSD3B1 mRNA and protein in HT-29 colon cancer cells. To figure out the potential signaling molecules involved in IL-4-induced HSD3B1 expression, we pre-treated HT-29 with various kinase inhibitors. Real-time RT-PCR data revealed that IL-4-induced HSD3B1 expression was markedly attenuated by GSK3 inhibitor CHIR99021 at late stage (10-24 hours). GSK3 activity is regulated by PI3k/Akt pathway. Western blot data revealed that IL-4 induced a rapid and transient phosphorylation of Akt-Ser473 (active form) and GSK3β-Ser9 (inactive form). PI3K inhibitor LY294002 strongly decreased IL-4-induced HSD3B1 expression at early stage (4 hours), whereas the mRNA level of HSD3B1 was slowly increased at late stage. These data suggested that IL-4 stimulated HSD3B1 via activation of PI3K/Akt activity declined later, accompanied by increased GSK3 activation that further promoted HSD3B1 expression. In addition, we found that IKK inhibitor BMS345541 completely abolished the production of HSD3B1 mRNA by IL-4 within 24 hours. IKK is known to activate the NF-κB downstream gene expression, and treatment with NF-κB inhibitor Bay117082 reduced the IL-4-induced HSD3B1 mRNA by 50%. However, the activation of NF-κB pathway by IL-4, including IκB degradation, NF-κB-p65 nuclear translocation and NF-κB-p100/p52 processing was not detected in HT-29 cells. In addition to HSD3B1, IL-4 also promoted the expression of steroidogenic genes required for glucocorticoid synthesis. We therefore analyzed the culture supernatant for the presence of GC. Using a GC bioassay, we showed that HT-29 cells could secrete bioactive GC by IL-4. Overall, this study demonstrates that IKK and PI3K/Akt/GSK3 signaling pathway are critical for IL-4-induced HSD3B1 expression that may account for the synthesis of bioactive GCs in colon cancer cells. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:49:34Z (GMT). No. of bitstreams: 1 ntu-106-R04441003-1.pdf: 2323774 bytes, checksum: e3cee11d472cbaaa310d137187809484 (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 致謝 I
目錄 II 表次 IV 圖次 IV 摘要 V Abstract VII 第一章 序論 1 一、類固醇荷爾蒙 1 二、腸道類固醇荷爾蒙的生成與作用 1 三、HSD3B簡介 2 1. 人類HSD3B基因 2 2. HSD3B基因的調控 3 四、IL-4簡介 4 1. IL-4的生理功能 4 2. IL-4的受體 4 3. IL-4的訊息傳遞路徑 4 五、GSK3訊息傳遞路徑 5 六、IKK訊息傳遞路徑 6 1. IKK的功能 6 2. IKK的調控 7 七、研究目的 8 第二章 材料與方法 9 一、藥品 9 二、細胞培養 10 三、蛋白質萃取 10 四、西方墨點法 (Western blot) 12 五、RNA萃取 14 六、即時性反轉錄聚合酶連鎖反應 (Real-time RT-PCR) 14 七、暫時性轉染法 (Transient transfection) 16 八、糖類皮質素活性分析 (GCs bioassay) 17 九、shRNA knockdown 18 十、統計分析 (Statistical analysis) 19 第三章 結果 20 一、IL-4增加HSD3B1的表現量 20 二、IL-4對於類固醇生成基因表現的影響 20 三、STAT6抑制劑對於IL-4誘導HSD3B1表現的影響 21 四、激酶抑制劑對於IL-4誘導HSD3B1表現的影響 21 五、GSK3抑制劑會降低IL-4誘導HSD3B1的表現 21 六、PI3K/Akt訊息傳遞路徑參與IL-4誘導HSD3B1表現 22 七、IKK抑制劑會降低IL-4誘導HSD3B1的表現 23 八、IL-4促進具生物活性的糖類皮質素分泌 24 第四章 討論 25 一、IL-4誘導HSD3B1表現的機制 25 1. PI3K/AKT/GSK3訊息傳遞路徑之作用 25 2. IKK訊息傳遞路徑之作用 25 3. IKK與PI3K/Akt/GSK3訊息傳遞路徑之間的關係 26 二、IL-4促進糖類皮質素分泌之作用 27 參考文獻 29 | |
dc.language.iso | zh-TW | |
dc.title | Interleukin-4誘導HT-29人類大腸癌細胞HSD3B1基因表現 | zh_TW |
dc.title | Interleukin-4 induces HSD3B1 expression in HT-29 human colon cancer cells | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 余佳慧(Chia-Hui Yu),徐立中(Li-Chung Hsu),張淑芬(Shwu-Fen Chang) | |
dc.subject.keyword | 介白素-4,HSD3B1,大腸癌,糖類皮質素, | zh_TW |
dc.subject.keyword | Interleukin-4,HSD3B1,Colon cancer,Glucocorticoid, | en |
dc.relation.page | 54 | |
dc.identifier.doi | 10.6342/NTU201703856 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-17 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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