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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77806完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 吳漢忠 | zh_TW |
| dc.contributor.author | 陳皓年 | zh_TW |
| dc.contributor.author | Hao-Nien Chen | en |
| dc.date.accessioned | 2021-07-11T14:35:11Z | - |
| dc.date.available | 2024-02-28 | - |
| dc.date.copyright | 2018-10-11 | - |
| dc.date.issued | 2018 | - |
| dc.date.submitted | 2002-01-01 | - |
| dc.identifier.citation | Horita, H., A. Law, S. Hong and K. Middleton (2017). "Identifying Regulatory Posttranslational Modifications of PD-L1: A Focus on Monoubiquitinaton." Neoplasia 19(4): 346-353.
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Pharmacol Ther 164: 152-169. Yamamoto, H., K. Higasa, M. Sakaguchi, K. Shien, J. Soh, K. Ichimura, M. Furukawa, S. Hashida, K. Tsukuda, N. Takigawa, K. Matsuo, K. Kiura, S. Miyoshi, F. Matsuda and S. Toyooka (2014). "Novel germline mutation in the transmembrane domain of HER2 in familial lung adenocarcinomas." J Natl Cancer Inst 106(1): djt338. Yeo, C. D., N. Kang, S. Y. Choi, B. N. Kim, C. K. Park, J. W. Kim, Y. K. Kim and S. J. Kim (2017). "The role of hypoxia on the acquisition of epithelial-mesenchymal transition and cancer stemness: a possible link to epigenetic regulation." Korean J Intern Med 32(4): 589-599. Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2014, National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2014/, based on November 2016 SEER data submission, posted to the SEER web site, April 2017. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77806 | - |
| dc.description.abstract | 肺癌為目前第二常見的癌症，而非小細胞肺癌約占其中之85%。目前肺癌為致死率第一的癌症，且五年存活率相較於其他癌症較小，因此必須發展更有效果的治療方式。臨床數據顯示阻斷PD-1/PD-L1能有效的延長肺癌病人的生存率，因此深入探討調控PD-L1表現的機制有助於我們發展合併用藥以達到更好的治療效果。先前，實驗室發現上皮細胞黏附因子(EpCAM)對於上皮生長因子受器(EGFR)及其下游訊號的活化非常重要，且有文獻指出EGFR對於PD-L1表現甚為重要。因此，本研究想探討上皮細胞黏附因子是否透過EGFR影響PD-L1之表現。首先，我們發現在相較於EpCAM低度表現的H460中，PD-L1蛋白在高度表達EpCAM 的H441的細胞中較為穩定。之後，在過量表達EpCAM的細胞中，PD-L1蛋白穩定性較好；相反的，抑制EpCAM表現的細胞中，PD-L1蛋白穩定性較差。隨後，我們發現外加EpCAM胞外結構(EpEX)會增加PD-L1蛋白表現，抑制內生性EpEX生成則會減少PD-L1蛋白表現，但是RNA表現皆無明顯差異。因此，我們認為EpEX主要會增加PD-L1蛋白穩定性。我們更進一步利用抑制劑發現EpEX主要是透過EGFR-ERK影響PD-L1蛋白表現。先前文獻指出ERK可能會增加泛素(ubiquitin)對於PD-L1蛋白之修飾，可是詳細機制尚不清楚。目前，我們將高度保留的lysine以點突變的方式確認K89R會使PD-L1蛋白不穩定且對於EpEX的刺激和抑制ERK的訊號皆無反應。且利用液相層析串聯式質譜儀(LC/MS/MS)確認K89上有ubiquitin之修飾。因此，我們認為PD-L1 K89對於EpEX調羫PD-L1穩定性中扮演重要腳色。另外，我們發現癌細胞在缺氧狀態時，ADAM17和 -secretase 會被活化且裁切出更多的EpEX，進而增加EGFR-ERK的活化。再者，活化之ERK能更增加PD-L1蛋白之表現；將PD-L1 K89突變後，PD-L1蛋白表現在缺氧狀態或是抑制ERK訊號後無明顯變化。 | zh_TW |
| dc.description.abstract | Lung cancer is the second most-common cancer and Non-Small Cell Lung cancer (NSCLC) accounts for aproximately 85% of all lung cancer cases. Lack of effective treatment contributes to NSCLC associated mortality. PD-L1/PD-1 inhibitors as a treatment modality for NSCLC had shown promise in clinical trials. Investigating the underlining mechanism of PD-L1 expression may assist the development of combinational therapies to improve the treatment efficacy for NSCLC. Several studies have shown that Epidermal Growth Factor Receptor (EGFR) signaling pathway is involved in the regulation of PD-L1 expression. Our previous studies have demonstrated that Epithelial Cell Adhesion Molecule (EpCAM) plays a crucial role in the activation of EGFR and its downstream gene expression. But the detailed mechanism remains elusive. In this study, we investigated whether EpCAM modulated PD-L1 expression through EGFR signaling pathway and attempted to uncover the underlining mechanism. We found that the stability of PD-L1 was much lower in H460, an NSCLC cell line with no EpCAM expression, than H441, an NSCLC cell line with high EpCAM expression. While EpCAM overexpression could stabilize PD-L1 protein, and PD-L1 destabilization was observed in EpCAM knockdown cells. We also observed that EpEX increased PD-L1 protein but not mRNA expression. Furthermore, our studies on EGFR and the inhibitor of its downstream gene revealed that EpEX-mediated PD-L1 expression was facilitated through the EGFR-ERK (extracellular-signal-regulated kinase) signaling pathway. Previous studies showed that monoubiquitination of PD-L1 through ERK signaling contributed to its stabilization. To elucidate the mechanism, we mutated ten highly conserved Lysine residues in PD-L1 and found that K89R led to unstable PD-L1. Also, K89R could not response to EpEX stimulation and ERK inhibition. Next, we used LC/MS/MS to confirm that K89 was modified by ubiquitin. Therefore, we concluded that PD-L1 K89 played a crucial role in EpEX-mediated PD-L1 induction. Furthermore, we found that HIF1α could enhance EpCAM cleavage and release soluble EpEX through ADAM17 and -secretase activation. HIF1α-mediated EpEX releasing could increase PD-L1 protein expression through ERK signal. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-11T14:35:11Z (GMT). No. of bitstreams: 1 ntu-107-R05450008-1.pdf: 2491872 bytes, checksum: 294fa4539b21f8a064b0f41cf4ac9f9a (MD5) Previous issue date: 2018 | en |
| dc.description.tableofcontents | 中文摘要...........................................................................................................................2
Abstract …………………………………………………………………………...…….3 Contents…………………………………………………………………………………5 Content of figures……………………………………………………………………….8 List of abbreviations…………………………………………………...……………...10 Introduction 1.1 Epidemiology of lung cancer……………………………………….………..12 1.2 Pathogenesis of lung cancer………………………………………...………..12 1.3 Treatments of lung cancer……………………………………………………14 1.4 Targeted therapy…………………………………………………….……….15 1.5 Immunotherapy ……………………………………………………...……...20 1.6 Anti- PD-1/PD-L1 therapy and NSCLC..........................................................21 1.7 PD-L1 expression…………………………………………………………....23 1.8 Epithelial cell adhesion molecule……………………………………………25 1.9 The expression of EpCAM……………………………………………..…....26 1.10 The signaling of EpCAM…………………………………………………….28 1.11 EpCAM and hypoxia-induced epithelial-to-mesenchymal transition………..30 Specific aims ……………………………………………………………………....32 Materials and methods 2.1 Cell lines and culture condition…………………………………...…………33 2.2 Flow cytometry analysis……………………………………………...…..….33 2.3 Production and purification of EpEX-Fc recombinant protein………......…..34 2.4 Immunoprecipitation assay…………………………………………………..34 2.5 Lentivirus-mediated short hairpin RNA (shRNA) knockdown……………....34 2.6 RNA extraction, cDNA synthesis, quantitative reverse transcription polymerase chain reaction (qRT-PCR)………………………………………35 2.7 Western blotting………………………………………...…………………...36 2.8 Immunofluorescence assay………………………………………….……….37 2.9 Cycloheximide chase assay………………………………………………….37 2.10 Statistical analysis……………………………………………...…………....38 Results 3.1 EpCAM expression is correlate PD-L1 stabilization…………………….......39 3.2 EpEX is crucial for PD-L1 stabilization……………………………….……..40 3.3 EpEX-mediated PD-L1 induction is through EGFR-ERK signal pathway......42 3.4 Identifying the EpEX regulation site in PD-L1……………………………....44 3.5 HIF1α enhance the RIP of EpCAM through ADAM17 transcription and -secretase activation…………………………………………………………..47 3.6 EpEX is crucial for EGFR signal activation and PD-L1 stabilization under hypoxia…………………………………………...………………………….48 Discussion………………………………………………………………………...……50 Figures……………………………………………………………………..………….. 61 References…………………………………………………...…………………………84 | - |
| dc.language.iso | en | - |
| dc.subject | 上皮細胞黏附因子 | zh_TW |
| dc.subject | 轉譯後修飾 | zh_TW |
| dc.subject | 缺氧 | zh_TW |
| dc.subject | 程序性細胞死亡-配體1 | zh_TW |
| dc.subject | 非小細胞肺癌 | zh_TW |
| dc.subject | Epithelial cell adhesion molecule (EpCAM) | en |
| dc.subject | hypoxia | en |
| dc.subject | post-translational modification | en |
| dc.subject | PD-L1 | en |
| dc.subject | Non-small-cell lung cancer | en |
| dc.title | 在非小細胞肺癌中上皮黏附因子增加程序性死亡-配體1之蛋白穩定性 | zh_TW |
| dc.title | EpCAM stabilizes PD-L1 protein in NSCLC | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 106-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 王逸平;林國儀 | zh_TW |
| dc.contributor.oralexamcommittee | ;; | en |
| dc.subject.keyword | 非小細胞肺癌,上皮細胞黏附因子,程序性細胞死亡-配體1,轉譯後修飾,缺氧, | zh_TW |
| dc.subject.keyword | Non-small-cell lung cancer,Epithelial cell adhesion molecule (EpCAM),PD-L1,post-translational modification,hypoxia, | en |
| dc.relation.page | 104 | - |
| dc.identifier.doi | 10.6342/NTU201801223 | - |
| dc.rights.note | 未授權 | - |
| dc.date.accepted | 2018-07-02 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 口腔生物科學研究所 | - |
| dc.date.embargo-lift | 2028-12-30 | - |
| 顯示於系所單位： | 口腔生物科學研究所 | |
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