請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/83333
標題: | RhoA異型體2位點R176G上核糖核酸編輯致體細胞突變促進肺腺癌腫瘤發展 Somatic RNA-edited RHOA isoform 2-R176G variant promotes tumor progression in lung adenocarcinoma |
其他標題: | Somatic RNA-edited RHOA isoform 2-R176G variant promotes tumor progression in lung adenocarcinoma |
作者: | 陳冠儒 Kuan-Ju Chen |
指導教授: | 周玉山 Yuh-Shan Jou |
關鍵字: | 肺腺癌,核糖核酸編輯事件,RHOA-R176G,SEQUENOM MassARRAY® System,Rock1/2, Lung adenocarcinoma,A-to-I RNA editing,RHOAiso2-R176G variant,SEQUENOM MassARRAY® System,Rock1/2, |
出版年 : | 2023 |
學位: | 博士 |
摘要: | (A-to-I) 核糖核酸編輯事件是在轉錄組中最常見的轉錄後核糖核酸編輯修飾,腺苷(Adenosine)轉換肌苷(Inosine)會造成體細胞突變和蛋白質組學的多樣性,然而其致癌性依舊極少探究。我們透過分析全基因組體細胞包含肺腺癌組織和配對的鄰近正常組織轉錄組中的(A-to-I) 核糖核酸編輯事件,一共得到26280個RNA編輯事件且主要發生在非編碼以及Alu重複的區域。其中體細胞(A-to-I)編輯事件造成的變異體包括AZIN1-S367G, RHOA-R176G, TUBGCP2-N211S and RBMXL1-I40M皆會形成錯義突變,而MDM2-UTR and PPIA-UTR則發生在3端非轉譯區,這些RNA編輯事件都能在RNA編輯資料庫以及藉由收集肺腺癌組織透過SEQUENOM MassARRAY® System方式驗證。有趣的是,體細胞A-to-I 核糖核酸編輯事件發生在RHOA上不僅會造成錯義突變且只發生在RhoA變異體2的3端上而不是在主要的RhoA變異體1上。進一步發現,有表現RHOAiso2-R176G比起表現RHOAiso2的肺腺癌病患轉錄組出現與調節異常的RHOA功能、細胞增生、細胞轉移以及臨床結果相關的基因提升。大量表現RHOAiso2-R176G在肺腺癌細胞株會透過增加RHOA-GTP的活性並增加下游Rock1/2的磷酸化來提升細胞的增生和轉移並且在異種移植實驗中增加腫瘤的生長和轉移。總體而言,當(A-to-I) RNA編輯事件發生在RHOAiso2-R176G會造成錯意突變且透過活化RHOA-GTP/p-ROCK1/2路徑能促進腫瘤發展,且可能成為在肺腺癌治療上針對蛋白異構體治療與診斷的標靶。 Adenosine to Inosine (A-to-I) RNA editing, the most common posttranscriptional editing in transcriptomes, causes somatic mutations and proteomic diversity but rarely explored their tumorigenicity. We conducted genome-wide somatic A-to-I RNA editing analysis of paired adjacent normal and lung adenocarcinoma (LUAD) transcriptomes and identified 26,280 editing events with majority of them residing in the non-coding and Alu repeat regions. Somatic A-to-I edited variants including AZIN1-S367G, RHOA-R176G, TUBGCP2-N211S and RBMXL1-I40M harbored nonsynonymous mutations, and MDM2-UTR and PPIA-UTR at the 3’ untranslated region were validated in databases and in SEQUENOM MassARRAY® System on newly collected LUAD tissues. Interestingly, somatic RHOA A-to-I RNA editing sites caused nonsynonymous mutations occurred mainly at the unique 3’-end RHOA isoform 2 RNA (RHOAiso2), but not RHOA major isoform 1. Upregulated genes of RHOAiso2-R176G-expressing LUAD patient transcriptomes, in compared with that of RHOAiso2, are associated with aberrant RHOA functions, proliferation, migration and clinical outcomes. Expression of RHOAiso2-R176G in LUAD cells potentiates RHOA-GTP activity to phosphorylate ROCK1/2 effectors and enhance cell proliferation and migration and increase tumor growth in xenograft and metastasis models. In summary, somatic A-to-I edited isoform 2 specific RHOAiso2-R176G mutation activated RHOA-GTP/p-ROCK1/2 signaling to promote tumor progression could be an isoform specific theranostic target in LUAD therapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/83333 |
DOI: | 10.6342/NTU202300461 |
全文授權: | 同意授權(全球公開) |
電子全文公開日期: | 2024-01-01 |
顯示於系所單位: | 微生物學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-111-1.pdf | 5.27 MB | Adobe PDF | 檢視/開啟 |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。