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標題: | 缺氧誘導之長片段非編碼核糖核酸NDRG1-OT1透過吸附微小核糖核酸miR-875-3p促進三陰性乳癌的進程 The Hypoxia-induced Long Non-coding RNA NDRG1-OT1 Acts as a Sponge of miR-875-3p to Promote Triple-negative Breast Cancer Progression |
作者: | Hsing-Hua Chao 趙幸華 |
指導教授: | 賴亮全(Liang-Chuan Lai) |
關鍵字: | 缺氧,缺氧誘導因子,三陰性乳癌,長片段非編碼核糖核酸,微小核糖核酸,功能,調控機制,胜肽, hypoxia,HIF-1α,triple-negative breast cancer,lncRNA,NDRG1-OT1,miRNA,miR-875-3p,STAT1,functions,regulatory mechanism,peptides, |
出版年 : | 2021 |
學位: | 碩士 |
摘要: | 乳癌是全球女性最容易罹外的癌症之一,其中又以三陰性乳癌最為惡性且最難以治療。許多研究指出:缺氧是使癌症變得更加惡性的環境因子之一,而長片段非編碼核糖核酸也參與了其中的機制。我們實驗室利用次世代定序技術(next generation sequencing)所找到並命名的一個當乳癌處於缺氧狀態時就會表現量上生的長片段非編碼核糖核酸(long non-coding RNA, lncRNA)──NDRG1-OT1便是其中一個重要角色,但它的詳細機轉和生物功能目前尚待釐清。過去我們實驗室發現了缺氧誘導因子1α (hypoxia-inducible factor α, HIF-1α)會使NDRG1-OT1的表現量上升,而在本篇論文中則驗證了當NDRG1-OT1的表現量大量上升之後會促進三陰性乳癌的惡化,包含增加三陰性乳癌細胞的生長速度、轉移能力、侵襲能力及促使周邊的血管新生以提供癌細胞更多的氧氣和養分。除了細胞實驗,也同時在移植了人類三陰性乳癌細胞的模式小鼠中證實大量表現NDRG1-OT1將會使腫瘤長得更快、更大。在機制的部分,我們發現NDRG1-OT1會透過吸附微小核糖核酸(micro RNA, miRNA)miR-875-3p來使得下游基因STAT1表現量上升,藉此促進三陰性乳癌的進程。此外,近年來越來越多的文獻報導有一些長片段非編碼核糖核酸是可以轉譯出胜肽的,且這些被轉譯出來的胜肽確實有其重要功能,這推翻了世人對於長片段非編碼核糖核酸原本的認知。本篇論文透過網站預測後發現NDRG1-OT1也是其中之一,並利用實驗證實NDRG1-OT確實能轉譯胜肽。綜合以上所述,NDRG1-OT1是一個在缺氧環境下會大量表現的lncRNA,在細胞核中它會透過HIF-1α來使得表現量上升;在細胞質內會吸附miR-875-3p使STAT1表現量上升,並轉譯出胜肽,最後促進三陰性乳癌的惡化。 Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide. Triple-negative breast cancer (TNBC) is the most aggressive and difficult to treat in all breast cancers. Hypoxia has been known to be a critical factor in the malignant progression of many cancers. In recent years, numerous studies indicated that long noncoding RNAs (lncRNA) were involved in a variety of biological functions and hypoxia induced the expression of many lncRNAs in breast cancer cells, including NDRG1-OT1 identified and named in our lab. However, their regulatory mechanism and biological functions remained elusive. Therefore, the purpose of this study was to investigate the transcriptional mechanism and potential functional roles of lncRNA NDRG1-OT1 in TNBC cells. Previously, we found that the hypoxia-inducible factor α (HIF-1α) bound at the NDRG1-OT1 promoter and enhanced the expression of NDRG1-OT1. In this study, using bioinformatics prediction and experimental validation, the results showed that NDRG1-OT1 acted as a sponge of miR-875-3p and upregulated the downstream target gene STAT1. Furthermore, many recent studies reported that some lncRNAs were able to translate small peptides to participate a wide range of biological processes. Our study also found that NDRG1-OT could translate small peptides. Lastly, overexpression of NDRG1-OT1 enhanced tumor progression by promoting cell proliferation, colony formation, migration and invasion capacity of triple-negative breast cancer cells, angiogenesis in human umbilical vein endothelial cells, and tumor growth in xenograft mouse models. Taken together, the hypoxia-induced lncRNA NDRG1-OT1 was transcriptionally regulated by HIF-1α in the nucleus, could translate small peptides and be sponged with miR-875-3p in the cytoplasm. In addition, NDRG1-OT1 promoted cell malignancy of triple-negative breast cancer cells. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69327 |
DOI: | 10.6342/NTU202100710 |
全文授權: | 有償授權 |
顯示於系所單位: | 生理學科所 |
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