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標題: | miR-21標的蛋白ASPP2其調控幽門螺旋桿菌誘導胃之機制與臨床相關性 The Mechanism and Clinical Relevance of miR-21 target ASPP2 in Helicobacter pylori-Induced Gastric Cancer |
作者: | 黃伯仕 Bo-Shih Huang |
指導教授: | 周綠蘋 Lu-Ping Chow |
關鍵字: | 幽門螺旋桿菌,胃癌,miR-21,ASPP2,抗凋亡, H. pylori,gastric cancer,miR-21,ASPP2,anti-apoptosis, |
出版年 : | 2023 |
學位: | 博士 |
摘要: | 幽門螺旋菌 (H. pylori) 感染會影響宿主細胞的存活途徑,包括細胞凋亡和增殖,而其失衡是H. pylori誘導胃癌 (HPGC) 發展的關鍵。H. pylori感染可誘導microRNAs表達的變化,其可能涉及GC的發展。生物資訊學分析顯示,在HPGC中microRNA-21(miR-21)表現顯著上升。此外,定量蛋白質體學和in silico預測被用於識別miR-21的潛在標的。透過功能富集和群集相互作用網絡分析,我們在與細胞死亡和存活,細胞運動以及細胞生長和增殖相關的三個功能簇中發現了miR-21標的之五個候選蛋白,PDCD4,ASPP2,DAXX,PIK3R1和MAP3K1。 H. pylori誘導的miR-21過度表達抑制ASPP2。此外,在HPGC腫瘤組織中,ASPP2與miR-21表現呈現負相關。總之,ASPP2在HPGC中被識別為miR-21的標的。在此,我們使用凋亡試驗觀察到H. pylori誘導的ASPP2抑制增強了GC細胞之抗凋亡能力。使用蛋白質相互作用網絡和免疫共沉澱實驗,我們發現了CHOP作為H. pylori感染的GC細胞中ASPP2促凋亡活性的直接介質。從機制上講,ASPP2抑制促進p300介導的CHOP降解,進而抑制CHOP介導的Noxa,Bak的轉錄和Bcl-2的抑制,進而在H. pylori感染之GC細胞中實現抗凋亡。臨床病理學分析顯示了ASPP2表達下降與HPGC風險增加和預後不良之間的相關性。綜合以上,我們發現H. pylori透過誘導miR-21介導的ASPP2 / CHOP介導信號之抑制來導致抗凋亡作用,此發現對於開發HPGC管理和治療策略提供了一個新的視角。 Helicobacter pylori (H. pylori) infection affects cell survival pathways, including apoptosis and proliferation in host cells, and disruption of this balance is the key event in the development of H. pylori-induced gastric cancer (HPGC). H. pylori infection induces alterations in microRNAs (miRNAs) expression that may be involved in GC development. Bioinformatic analysis showed that microRNA-21 (miR-21) is significantly upregulated in HPGC. Furthermore, quantitative proteomics and in silico prediction were employed to identify potential targets of miR-21. Following functional enrichment and clustered interaction network analyses, five candidates of miR-21 targets, PDCD4, ASPP2, DAXX, PIK3R1, and MAP3K1, were found across three functional clusters associated with cell death and survival, cellular movement, and cellular growth and proliferation. ASPP2 is inhibited by H. pylori-induced miR-21 overexpression. Moreover, ASPP2 is inversely correlated with miR-21 levels in HPGC tumor tissues. Taken together, ASPP2 was identified as a miR-21 target in HPGC. Here, we observed H. pylori-induced ASPP2 suppression enhances resistance to apoptosis in GC cells using apoptosis assays. Using protein interaction network and co-immunoprecipitation assay, we identified CHOP as a direct mediator of the ASPP2 pro-apoptotic activity in H. pylori-infected GC cells. Mechanistically, ASPP2 suppression promotes p300-mediated CHOP degradation, which in turn inhibits CHOP-mediated transcription of Noxa, Bak, and suppression of Bcl-2, leading to anti-apoptotic effects in GC cells after H. pylori infection. Clinicopathological analysis revealed correlations between decreased ASPP2 expression and higher HPGC risk and poor prognosis. In summary, the discovery of H. pylori-induced anti-apoptosis via miR-21-mediated suppression of ASPP2/CHOP-mediated signaling provides a novel perspective on developing HPGC management and treatment. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90338 |
DOI: | 10.6342/NTU202303084 |
全文授權: | 未授權 |
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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