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標題: | 整合系統型分析非編碼核糖核酸基揭露其在肺腺癌增加惡性腫瘤生成之潛在機制 Integrative analyses of noncoding RNAs disclose potential mechanisms augmenting tumor malignancy in lung adenocarcinoma |
作者: | Jou-Ho Shih 施柔合 |
指導教授: | 周玉山(Yuh-Shan Jou) |
關鍵字: | 具預後預測能力的ncRNA網絡,PTTG3P,抗藥性,FOXM1/BUB1B信息傳導,有絲分裂之中期到末期之過程, prognostic ncRNAs networks,PTTG3P,drug resistance,FOXM1/BUB1B signaling axis,metaphase-anaphase transition, |
出版年 : | 2019 |
學位: | 博士 |
摘要: | 肺癌是全球癌症十大死因中排名第一的癌症,因此開發能提高肺癌病人存活率的標靶仍具急迫性。非編碼核糖核酸 (ncRNA) 被研究指出在癌症腫瘤生成過程中顯示異常表現,然而對於ncRNA在腫瘤生成的確切機制未知之外且臨床應用仍屬匱乏。因此,發展ncRNA所設計之基因網絡來精準預測ncRNA之生物功能及致病機制實屬必要。在此篇研究,我們設計了一個系統化方法來偵測具診療預測性之ncRNA,並預測其在肺癌中最主要的亞型,肺腺癌中的生物功能並且探討他們的致病機制。多筆肺腺癌病人的資料藉由生物資訊分析以及實驗檢測之下來評估診斷ncRNA之預測能力,我們從六個具預測能力之ncRNA (MIR497HG, HSP078, TBX5-AS1, LOC100506990, and C14orf64) 當中選了在所有資料中數值最一致的PTTG3P來做後續之分子生物機制探討。PTTG3P 在肺腺癌細胞中高度表現並縮短細胞有絲分裂過程的中期到末期轉換時間,增加細胞對抗癌藥物包含順鉑(cisplatin)以及紫杉醇(paclitaxel)的耐受性,增加癌細胞增生導致肺部原位腫瘤小鼠動物模式傾向較差存活率。同時在癌症基因體圖譜計畫(TCGA)所收集到的病人中PTTG3P表現量較高的病人其接受化療時亦傾向較差存活率。從機制層面探討發現,PTTG3P ncRNA藉由調控轉錄因子FOXM1來調節有絲分裂檢查酵素BUB1B的轉錄活動,並藉此影響腫瘤增生,抗藥性以及導致肺腺癌病人的高死亡率。整體而言,我的論文研究建立了一個整合性策略來探討具預後預測之驅動ncRNA並預測他們的功能,而此方法可以適用於所有癌症研究。不僅如此,我的研究結果顯示出由於高表現的PTTG3P透過ncRNA/FOXM1/BUB1B細胞信息傳導而導致在肺腺癌病人低存活率,而這個可以被視為一個在肺腺癌病人當中很好的標靶治療目標。 Lung cancer is the most common cause of human cancer death worldwide with urgent needs of targets to prolong patient survival. Aberrant activation of non-coding RNAs (ncRNAs) during tumor progression remain functional unknown and thus limit clinical impacts. Precise ncRNA-based network prediction is necessary to reveal ncRNA cellular functions and pathological mechanisms. Here, we established a systemic approach to identify prognostic ncRNAs to predict their functions and explore their pathological mechanisms in lung adenocarcinoma (LUAD), which is the most predominant subtype of lung cancer. After in silico and experimental validation based on evaluations of prognostic value in multiple LUAD cohorts, we selected the PTTG3P pseudogene from among other prognostic ncRNAs (MIR497HG, HSP078, TBX5-AS1, LOC100506990, and C14orf64) for mechanistic studies. PTTG3P upregulation in LUAD cells shortened the metaphase to anaphase transition in mitosis, increases cell viability after cisplatin or paclitaxel treatment, facilitated tumor growth that led to poor survival in orthotopic lung models, and is associated with a poor survival rate in LUAD patients in The Cancer Genome Atlas (TCGA) cohort who received chemotherapy. Mechanistically, PTTG3P acts as an ncRNA that mediates the transcription factor FOXM1 to regulate the transcriptional activation of the mitotic checkpoint kinase BUB1B, which augments tumor growth and chemoresistance and leads to poor outcomes for LUAD patients. Overall, we established an integrative approach to uncover prognostic driver ncRNAs with functional prediction methods suitable for pancancer studies. Moreover, we revealed that PTTG3P, due to its upregulation of the ncRNA/FOXM1/BUB1B axis, could be a therapeutic target for LUAD patients. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/74185 |
DOI: | 10.6342/NTU201903353 |
全文授權: | 有償授權 |
顯示於系所單位: | 基因體與系統生物學學位學程 |
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