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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82733完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 阮雪芬(Hsueh-Fen Juan) | |
| dc.contributor.author | Chieh-Fan Yin | en |
| dc.contributor.author | 鄞偈帆 | zh_TW |
| dc.date.accessioned | 2022-11-25T07:58:39Z | - |
| dc.date.copyright | 2021-11-19 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-10-26 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82733 | - |
| dc.description.abstract | 胃癌是世界上許多人患有的癌症之一，然而目前尚未發現有效的治療策略。許多之前的研究顯示，從傳統草藥材：丹參 (Salvia miltiorrhiza) ，其中提取的丹參酮 IIA 可以對抗對多種癌症。在我們先前的研究結果有提到，丹參酮 IIA 會誘導胃癌細胞株走向細胞死亡，但是確切的訊號機制及其反應路徑仍不是非常清楚。而我們也知道在廣泛的癌症生理過程中，癌細胞的轉譯後修飾會發揮其重要作用去調節許多細胞相關的反應路徑以及訊號傳訊級聯反應。於是在本篇研究中，我們先是整合了轉錄體學和動態磷酸蛋白質體學，並以多體學的方式揭開胃癌細胞中由丹參酮 IIA 所觸發的調控網絡。接著我們確定了丹參酮 IIA 會導致熱休克蛋白 27 其絲氨酸 82 的位置磷酸化，從而導致活性氧的累積、蛋白折疊不全反應以及粒線體形態分裂。我們也從文獻上知道，線粒體在各種類型的細胞中的融合和分裂以及處於不同的環境或壓力下，線粒體會呈現高度動態的狀態。也有越來越多的證據提出，粒線體動態的失衡最後會導致多種人類相關癌症的死亡。因此，未來針對調控線粒體動態平衡可以說是一個有潛力的治療目標。從我們結果可以看到，細胞壓力的累積進一步增加了熱休克因子1的表達水平。而熱休克因子1 會同時參與熱休克壓力和細胞凋亡反應，其下游調控的基因也在丹參酮 IIA 處理組中被活化。總結來說，我們運用了多體學的方法在胃癌細胞中建立了以丹參酮 IIA 為影響因子的調控網絡。然後觀察到丹參酮 IIA 首先會透過增加熱休克蛋白 27 其絲氨酸 82 的位置磷酸化並對胃癌細胞產生壓力，接著活化胃癌細胞中熱休克因子1的反應路徑，最後誘導胃癌細胞往計畫性細胞死亡邁進。本篇研究為胃癌治療策略的開發上提供了全面性且有建設性的見解。 | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T07:58:39Z (GMT). No. of bitstreams: 1 U0001-0610202113311000.pdf: 62842570 bytes, checksum: 66dfac4f00351a86638b191c819d859a (MD5) Previous issue date: 2021 | en |
| dc.description.tableofcontents | 中文摘要 i Abstract ii Contents iv List of Tables vii List of Figures viii Chapter 1. Introduction 1 1.1 Gastric cancer 1 1.2 Tanshinone IIA 1 1.3 Phosphoproteomics 2 1.4 Mitochondrial dynamics 2 1.4.1 Mitochondrial fission 3 1.4.2 Mitochondrial fusion 5 1.5 Motivation 7 Chapter 2. Materials and Methods 8 2.1 Cell culture 8 2.2 Drug treatments 8 2.3 Cell line processing protocol for phosphoproteomic analysis 8 2.4 Dimethyl labeling of peptides 9 2.5 Enrichment of phosphopeptides 9 2.6 Strong cation exchange (SCX) chromatography of phosphopeptides 10 2.7 NanoLC−MS/MS analysis for phosphoproteome 10 2.8 Experimental design and statistical rationale for cell-line phosphoproteomes 11 2.9 Pathway enrichment analysis and functional profiling 12 2.10 Kinase enrichment analysis 13 2.11 Transcription factor enrichment analysis 14 2.12 Functional analysis of HSF1 targets 14 2.13 Proliferation assay 14 2.14 Flow cytometry detection of reactive oxygen species 15 2.15 Western blot analysis 15 2.16 Immunocytochemistry and image analysis 16 2.17 RNA extraction and cDNA preparation from cell cultures 16 2.18 Real-time polymerase chain reaction (RT-PCR) 17 2.19 Cloning and site-directed mutagenesis of HSP27 17 2.20 Cell Transfection 18 2.21 Statistical analysis 18 Chapter 3. Results 20 3.1 Overall experimental design for profiling the phosphoproteome and transcriptome regulated by TIIA in gastric cancer 20 3.2 Quantitative phosphoproteome response to TIIA treatment in gastric cancer 21 3.3 Functional networks of TIIA treatment-regulated proteins in gastric cancer 21 3.4 TIIA induced mitochondrial fission of AGS cells 23 3.5 Temporal TIIA treatment increased phosphorylation of HSP27 at serine 82 23 3.6 TIIA regulated relationship between phosphorylation of HSP27 and expression of HSF1 in long-term treatment 24 3.7 TIIA regulated HSF1-related genes during long-term treatment 25 Chapter 4. Discussion 26 Chapter 5. Conclusion 38 Reference 39 Tables 61 Figures 68 Appendix. Publication List 93 | |
| dc.language.iso | en | |
| dc.subject | 丹參酮IIA | zh_TW |
| dc.subject | 粒線體動態平衡 | zh_TW |
| dc.subject | 胃癌 | zh_TW |
| dc.subject | 熱休克因子1 | zh_TW |
| dc.subject | 粒線體分裂 | zh_TW |
| dc.subject | 癌症治療 | zh_TW |
| dc.subject | 粒線體融合 | zh_TW |
| dc.subject | 磷酸蛋白體 | zh_TW |
| dc.subject | 熱休克蛋白27 | zh_TW |
| dc.subject | Gastric cancer | en |
| dc.subject | Cancer therapy | en |
| dc.subject | Mitochondrial fusion | en |
| dc.subject | Mitochondrial fission | en |
| dc.subject | Mitochondria dynamics | en |
| dc.subject | Heat shock factor 1 (HSF1) | en |
| dc.subject | Heat shock protein 27 (HSP27) | en |
| dc.subject | Phosphoproteome | en |
| dc.subject | Tanshinone IIA | en |
| dc.title | 丹參酮 IIA 經由熱休克蛋白 27 之磷酸化與粒線體動態變化而誘導細胞死亡 | zh_TW |
| dc.title | Tanshinone IIA-Induced Cell Death via Heat Shock Protein 27 Phosphorylation and Mitochondria Dynamics | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 黃宣誠(Hsin-Tsai Liu),黃翠琴(Chih-Yang Tseng),張心儀,許家郎 | |
| dc.subject.keyword | 胃癌,丹參酮IIA,磷酸蛋白體,熱休克蛋白27,熱休克因子1,粒線體動態平衡,粒線體分裂,粒線體融合,癌症治療, | zh_TW |
| dc.subject.keyword | Gastric cancer,Tanshinone IIA,Phosphoproteome,Heat shock protein 27 (HSP27),Heat shock factor 1 (HSF1),Mitochondria dynamics,Mitochondrial fission,Mitochondrial fusion,Cancer therapy, | en |
| dc.relation.page | 114 | |
| dc.identifier.doi | 10.6342/NTU202103581 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2021-10-27 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| dc.date.embargo-lift | 2023-10-31 | - |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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