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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 賴亮全(Liang-Chuan Lai) | |
dc.contributor.author | Hsing-Hua Chao | en |
dc.contributor.author | 趙幸華 | zh_TW |
dc.date.accessioned | 2021-06-17T03:13:00Z | - |
dc.date.available | 2021-02-23 | |
dc.date.copyright | 2021-02-23 | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021-02-17 | |
dc.identifier.citation | 1 Siegel, R. L. et al. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7-34 (2019). 2 Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87-108 (2015). 3 Holliday, D. L. et al. Choosing the right cell line for breast cancer research. Breast Cancer Res. 13, 1-7 (2011). 4 Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747-752 (2000). 5 Kumar, P. et al. An overview of triple-negative breast cancer. Arch. Gynecol. Obstet. 293, 247-269 (2016). 6 Petrova, V. et al. The hypoxic tumour microenvironment. Oncogenesis 7, 1-13 (2018). 7 Pouysségur, J. et al. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441, 437-443 (2006). 8 Wang, F. et al. A novel hypoxia-induced miR-147a regulates cell proliferation through a positive feedback loop of stabilizing HIF-1α. Cancer Biol. Ther. 17, 790-798 (2016). 9 Liao, D. et al. Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 67, 563-572 (2007). 10 Volm, M. et al. Hypoxia-inducible factor (HIF-1) and its relationship to apoptosis and proliferation in lung cancer. Anticancer Res. 20, 1527-1533 (2000). 11 Jiang, Y. et al. The effect of silencing HIF-1α gene in BxPC-3 cell line on glycolysis-eelated gene expression, cell growth, invasion, and apoptosis. Nutr Cancer 67, 1316-1325 (2015). 12 da Motta, L. L. et al. The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene 36, 122-132 (2017). 13 Vaupel, P. et al. Hypoxia-/HIF-1α-driven factors of the tumor microenvironment impeding antitumor immune responses and promoting malignant progression. Springer.171-175 (2018). 14 Jing, X. et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol. Cancer 18, 157 (2019). 15 Lundgren, K. et al. Hypoxia and breast cancer: prognostic and therapeutic implications. Cell Mol Life Sci 64, 3233-3247 (2007). 16 Thomas, D. D. et al. Hypoxic inducible factor 1α, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide. Proc. Natl. Acad. Sci. U.S.A. 101, 8894-8899 (2004). 17 Tam, S. Y. et al. Hypoxia-induced epithelial-mesenchymal transition in cancers: HIF-1α and beyond. Front. Oncol. 10, 486 (2020). 18 Lu, C.-W. et al. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol. Chem. 283, 28106-28114 (2008). 19 Uszczynska-Ratajczak, B. et al. Towards a complete map of the human long non-coding RNA transcriptome. Nat. Rev. Genet. 19, 535-548 (2018). 20 Lau, E. Non-coding RNA: zooming in on lncRNA functions. Nat. Rev. Genet. 15, 574 (2014). 21 Lee, J. T. Epigenetic regulation by long noncoding RNAs. Science 338, 1435-1439 (2012). 22 Huarte, M. The emerging role of lncRNAs in cancer. Nat. Med. 21, 1253-1261 (2015). 23 Schmitt, A. M. et al. Long noncoding RNAs in cancer pathways. Cancer cell 29, 452-463 (2016). 24 Kuo, T. C. et al. Signaling in and out: long-noncoding RNAs in tumor hypoxia. J. Biomed. Sci. 27, 1-25 (2020). 25 Niu, Y. et al. HIF2-Induced long noncoding RNA RAB11B-AS1 promotes hypoxia-mediated angiogenesis and breast cancer metastasis. Cancer Res. 80, 964-975 (2020). 26 Wang, S. et al. Hypoxia-induced lncRNA PDIA3P1 promotes mesenchymal transition via sponging of miR-124-3p in glioma. Cell Death Dis 11, 1-17 (2020). 27 Deng, S. j. et al. Hypoxia-induced lncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription. Oncogene 37, 5811-5828 (2018). 28 Lin, H. C. et al. The hypoxia-responsive lncRNA NDRG-OT1 promotes NDRG1 degradation via ubiquitin-mediated proteolysis in breast cancer cells. Oncotarget 9, 10470 (2018). 29 Luo, J. L. 探討長片段非編碼核糖核酸 NDRG1-OT1 在乳癌細胞中的調控機制與扮演的功能角色. 臺灣大學生理學研究所學位論文, 1-64 (2018). 30 Yeh, C. C. et al. Different effects of long noncoding RNA NDRG1-OT1 fragments on NDRG1 transcription in breast cancer cells under hypoxia. RNA Biol 15, 1487-1498 (2018). 31 Noh, J. H. et al. Cytoplasmic functions of long noncoding RNAs. Wiley Interdiscip Rev RNA 9, e1471 (2018). 32 Rashid, F. et al. Long non-coding RNAs in the cytoplasm. Genomics, proteomics bioinformatics 14, 73-80 (2016). 33 Wu, P. et al. Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol Cancer 19, 22 (2020). 34 Wang, J. et al. NcRNA-encoded peptides or proteins and cancer. Mol Ther 27, 1718-1725 (2019). 35 Huang, J. Z. et al. A peptide encoded by a putative lncRNA HOXB-AS3 suppresses colon cancer growth. Mol Cell 68, 171-184 e176 (2017). 36 Maxwell, P. et al. Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc. Natl. Acad. Sci. U.S.A. 94, 8104-8109 (1997). 37 Ryan, H. E. et al. Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Res. 60, 4010-4015 (2000). 38 Lin, H. C. et al. Hypoxic long noncoding RNA NDRG1-OT1 inhibit NDRG1 in MCF-7 breast cancer cell line. AARC 76, 975 (2016). 39 Agarwal, V. et al. Predicting effective microRNA target sites in mammalian mRNAs. eLife 4, e05005 (2015). 40 Parsons, C. et al. The role of long noncoding RNAs in cancer metastasis. J Cancer Metastasis Treat 4, 19 (2018). 41 Rathinasamy, B. et al. Role of lncRNAs in the cancer development and progression and their regulation by various phytochemicals. Biomed. Pharmacother. 102, 242-248 (2018). 42 Choudhari, R. et al. Long noncoding RNAs in cancer: From discovery to therapeutic targets.Elsevier. 95,105-147 (2020). 43 Do, H. et al. Roles of oncogenic long non-coding RNAs in cancer development. Genomics Inform. 16 (2018). 44 Huang, Z. et al. H19 promotes non‐small‐cell lung cancer (NSCLC) development through STAT3 signaling via sponging miR‐17. J. Cell. Physiol. 233, 6768-6776 (2018). 45 Li, S. et al. Pan-cancer analysis of long non-coding RNA NEAT1 in various cancers. Genes diseases 5, 27-35 (2018). 46 Cai, Y. et al. Long noncoding RNA CCAT2 promotes breast tumor growth by regulating the Wnt signaling pathway. OncoTargets Ther. 8, 2657 (2015). 47 Sun, M. et al. Downregulation of BRAF activated non-coding RNA is associated with poor prognosis for non-small cell lung cancer and promotes metastasis by affecting epithelial-mesenchymal transition. Mol. Cancer 13, 1-12 (2014). 48 Han, L. Low expression of long noncoding RNA PANDAR predicts a poor prognosis of non-small cell lung cancer and affects cell apoptosis by regulating Bcl-2. Cell Death Disease 6, e1665 (2015). 49 Lu, K. h. et al. Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC cancer 13, 461 (2013). 50 Gilkes, D. M. et al. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat. Rev. Cancer 14, 430-439 (2014). 51 Mi, L. et al. The metastatic suppressor NDRG1 inhibits EMT, migration and invasion through interaction and promotion of caveolin-1 ubiquitylation in human colorectal cancer cells. Oncogene 36, 4323-4335 (2017). 52 Zhang, S. et al. N-myc downstream-regulated gene 1 inhibits the proliferation of colorectal cancer through emulative antagonizing NEDD4-mediated ubiquitylation of p21. J. Exp. Clin. Cancer Res. 38, 1-15 (2019). 53 Lin, H. C. et al. The hypoxia-responsive lncRNA NDRG-OT1 promotes NDRG1 degradation via ubiquitin-mediated proteolysis in breast cancer cells. Oncotarget 9, 10470-10482 (2018). 54 Li, D. et al. PF4V1, an miRNA-875-3p target, suppresses cell proliferation, migration, and invasion in prostate cancer and serves as a potential prognostic biomarker. Cancer Manag. Res. 11, 2299 (2019). 55 Li, S. et al. MiRNA-875-3p alleviates the progression of colorectal cancer via negatively regulating PLK1 level. Eur. Rev. Med. Pharmacol. Sci. 24, 1126-1133 (2020). 56 Wang, W. et al. Circular RNA circ-FOXP1 induced by SOX9 promotes hepatocellular carcinoma progression via sponging miR-875-3p and miR-421. Biomed. Pharmacother. 121, 109517 (2020). 57 Zhang, Y. et al. STAT1 in cancer: friend or foe? Discov. Med. 24, 19-29 (2017). 58 Adamkova, L. et al. Transcription protein STAT1: biology and relation to cancer. Folia Biol. 53, 1 (2007). 59 Chen, J. et al. STAT1 modification improves therapeutic effects of interferons on lung cancer cells. J. Transl. Med. 13, 1-10 (2015). 60 Dorritie, K. et al. STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia 28, 248-257 (2014). 61 Zhang, X. et al. STAT1 inhibits MiR‐181a expression to suppress colorectal cancer cell proliferation through PTEN/Akt. J. Cell. Biochem. 118, 3435-3443 (2017). 62 Zhang, Y. et al. The clinical and biological significance of STAT1 in esophageal squamous cell carcinoma. BMC cancer 14, 1-14 (2014). 63 Zhang, Y. et al. Correlation of STAT1 with apoptosis and cell-cycle markers in esophageal squamous cell carcinoma. PLoS One 9, e113928 (2014). 64 Magkou, C. et al. Prognostic significance of phosphorylated STAT‐1 expression in premenopausal and postmenopausal patients with invasive breast cancer. Histopathology 60, 1125-1132 (2012). 65 Khodarev, N. et al. Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer. Oncogene 29, 920-929 (2010). 66 Duarte, C. W. et al. Expression signature of IFN/STAT1 signaling genes predicts poor survival outcome in glioblastoma multiforme in a subtype-specific manner. PLoS One 7, e29653 (2012). 67 Zimmerman, M. A. et al. Unphosphorylated STAT1 promotes sarcoma development through repressing expression of Fas and bad and conferring apoptotic resistance. Cancer Res. 72, 4724-4732 (2012). 68 Liu, Z. et al. The reciprocal interaction between LncRNA CCAT1 and miR-375-3p contribute to the downregulation of IRF5 gene expression by solasonine in HepG2 human hepatocellular carcinoma cells. Front. Oncol. 9, 1081 (2019). 69 Ulitsky, I. Interactions between short and long noncoding RNAs. FEBS Lett. 592, 2874-2883 (2018). 70 Jonas, S. et al. Towards a molecular understanding of microRNA-mediated gene silencing. Nat. Rev. Genet. 16, 421-433 (2015). 71 Figliuzzi, M. et al. MicroRNAs as a selective channel of communication between competing RNAs: a steady-state theory. Biophys. J. 104, 1203-1213 (2013). 72 Batista, P. J. et al. Long noncoding RNAs: cellular address codes in development and disease. Cell 152, 1298-1307 (2013). 73 Rinn, J. L. et al. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem. 81, 145-166 (2012). 74 Ulitsky, I. et al. lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26-46 (2013). 75 Choi, S. W. et al. The small peptide world in long noncoding RNAs. Brief. Bioinformatics 20, 1853-1864 (2019). 76 Wang, J. et al. NcRNA-encoded peptides or proteins and cancer. Mol. Ther. 27, 1718-1725 (2019). | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/69327 | - |
dc.description.abstract | 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。 | zh_TW |
dc.description.abstract | 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. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T03:13:00Z (GMT). No. of bitstreams: 1 U0001-1702202101165400.pdf: 3558990 bytes, checksum: be67e59b54dec940f2a6bc67be1c3ab1 (MD5) Previous issue date: 2021 | en |
dc.description.tableofcontents | 致謝----------------------------------------------------------------------------I 摘要--------------------------------------------------------------------------III Abstract-----------------------------------------------------------------------IV List of Tables-----------------------------------------------------------------IX List of Figures-----------------------------------------------------------------X Chapter 1. Introduction---------------------------------------------------------1 1.1 Triple-negative breast cancer and the hypoxic tumor microenvironment----1 1.2 The hypoxia-induced long non-coding RNAs in cancer----------------------3 1.3 The functions and regulatory mechanism of NDRG1-OT1 in breast cancer----4 1.4 The aim of this study---------------------------------------------------5 Chapter 2. Materials and Methods------------------------------------------------7 2.1 Cell culture and treatment----------------------------------------------7 2.2 Plasmid construction and cell transfection------------------------------7 2.3 RNA extraction, reverse transcription and quantitative RT-PCR-----------9 2.4 MTT assay--------------------------------------------------------------10 2.5 Colony formation assay-------------------------------------------------10 2.6 Wound healing assay----------------------------------------------------11 2.7 Transwell migration assay----------------------------------------------11 2.8 Transwell invasion assay-----------------------------------------------12 2.9 Tube formation assay---------------------------------------------------13 2.10 Cell cycle analysis----------------------------------------------------13 2.11 Induction of cell apoptosis--------------------------------------------14 2.12 Xenograft and bioluminescent imaging-----------------------------------14 2.13 Nuclear-cytoplasmic RNA fractionation----------------------------------15 2.14 RNA immunoprecipitation (RIP)------------------------------------------16 2.15 Luciferase reporter assay----------------------------------------------17 2.16 Western blot analysis--------------------------------------------------18 2.17 Immunofluorescence-----------------------------------------------------19 2.18 Statistical analysis---------------------------------------------------20 Chapter 3. Results-------------------------------------------------------------21 3.1 NDRG1-OT1 promoted cell proliferation, colony formation, migration and invasion in MDA-MB-231 cells and angiogenesis in HUVECs------------------------21 3.2 NDRG1-OT1 served as miRNA sponge to upregulate STAT1 by directly interacting with miR-875-3p----------------------------------------------------------------22 3.3 miR-875-3p inhibited NDRG1-OT1 through binding at 438-445 nucleotide of NDRG1-OT1----------------------------------------------------------------------24 3.4 NDRG1-OT1 promoted triple-negative breast cancer progression through acting as a sponge of miR-875-3p------------------------------------------------------25 3.5 NDRG1-OT1 translated small peptides------------------------------------25 Chapter 4. Discussion----------------------------------------------------------27 4.1. NDRG1-OT1 played a role of oncogene in triple-negative breast cancer---27 4.2. NDRG1-OT1 acted as a sponge of miR-875-3p to promote triple-negative breast cancer progression through regulating STAT1 expression-------------------------28 4.3. Reciprocal inhibition on NDRG1-OT1 and miR-875-3p----------------------30 4.4. Translational ability of NDRG1-OT1-------------------------------------30 4.5. Limitations of this study----------------------------------------------31 4.6. Conclusion-------------------------------------------------------------32 Tables-------------------------------------------------------------------------33 Figures------------------------------------------------------------------------36 References---------------------------------------------------------------------51 | |
dc.language.iso | en | |
dc.title | 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 | zh_TW |
dc.title | The Hypoxia-induced Long Non-coding RNA NDRG1-OT1 Acts as a Sponge of miR-875-3p to Promote Triple-negative Breast Cancer Progression | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 碩士 | |
dc.contributor.advisor-orcid | 賴亮全(0000-0002-3913-5338) | |
dc.contributor.oralexamcommittee | 蔡孟勳(Mong-Hsun Tsai),陳立涵(Li-Han Chen),佘玉萍(Yuh-Pyng Sher) | |
dc.subject.keyword | 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, | zh_TW |
dc.subject.keyword | hypoxia,HIF-1α,triple-negative breast cancer,lncRNA,NDRG1-OT1,miRNA,miR-875-3p,STAT1,functions,regulatory mechanism,peptides, | en |
dc.relation.page | 55 | |
dc.identifier.doi | 10.6342/NTU202100710 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2021-02-18 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
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