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系統識別號 U0026-2907201602184700
論文名稱(中文) 微核醣核酸455-5p在口腔腫瘤生成中所扮演之角色
論文名稱(英文) The role of miR-455-5p in the tumorigenesis of oral cancer
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 104
學期 2
出版年 105
研究生(中文) 鄭昭旻
研究生(英文) Chao-Min Cheng
電子信箱 s58981329@mail.ncku.edu.tw
學號 s58981329
學位類別 博士
語文別 英文
論文頁數 66頁
口試委員 指導教授-張俊彥
口試委員-陳玉玲
口試委員-吳昭良
口試委員-洪文俊
口試委員-謝義興
中文關鍵字 口腔癌  微核醣核酸455-5p  轉化生長因子-β 
英文關鍵字 oral cancer  UBE2B  miR-455-5p  TGF-β 
學科別分類
中文摘要 口腔癌新生案例目前在全世界有逐年增加的趨勢,且在台灣惡性腫瘤死亡原因中高居前十位。口腔癌晚期病人的五年存活率不到50%,因此了解口腔癌的發生成因和尋找適合的診斷及預後生物標記是現今治療口腔癌的當務之急。近十年來研究已知可以利用腫瘤和正常組織裡特定微核醣核酸的表現量作為一種新的生物標記。目前微核醣核酸在口腔癌中所扮演的角色還鮮少被探討,於是本研究計畫是利用口腔癌病人檢體作篩選,挑出微核醣核酸-455-5p,其表現量在腫瘤組織中明顯高於正常組織,且在口腔癌細胞株中的表現量也高於正常口腔表皮細胞。我們也發現抑制微核醣核酸-455-5p可以降低癌細胞在軟性瓊脂裡形成聚落的能力,也抑制了細胞增生能力。證明微核醣核酸-455-5p在正常細胞轉型為癌細胞的過程中扮演重要的角色。藉由細胞株大量表現微核醣核酸-455-5p和病人檢體的微陣列資料,加上網路軟體預測結果相互交集,分析出可能的下游目標基因。接著利用西方點墨法和冷光報導實驗證實UBE2B是微核醣核酸-455-5p的目標基因。從軟性瓊脂和細胞增生實驗也進一步證實,微核醣核酸-455-5p確實是透過控制UBE2B而達到影響癌細胞生長能力。由腫瘤微環境分泌的轉化生長因子-β已知參與在腫瘤新生、惡化到最後的轉移過程;且在口腔癌中轉化生長因子-β如何藉由調控微核醣核酸造成腫瘤進程的機制目前也還不清楚。我們利用即時定量聚合酶連鎖反應偵測到微核醣核酸-455-5p會受到轉化生長因子-β刺激而增加,進而改變下游UBE2B表現量,而且中間是藉由SMAD3來調控。在動物的腫瘤實驗中也顯示微核醣核酸-455-5p和UBE2B的確可以調控口腔癌腫瘤生長情形,在已發表文獻中也發現UBE2B在腫瘤組織裡的表現量低於正常組織。甚至在臨床資料中也發現微核醣核酸-455-5p表現量較高的病患其預後情況較差。在本篇報告中我們利用臨床病人檢體資料,搭配生物資訊分析和細胞實驗,指出轉化生長因子-β和缺氧環境會調控微核醣核酸-455-5p增加,而且是藉由改變UBE2B表現量來達到影響腫瘤生長的結果。
英文摘要 Oral cancer ranks the fourth common cause of cancer death for men in Taiwan, and the incidence is increasing year by year. The standard treatment for patients in late stage is concurrent chemoradiotherapy. The major causes of death in oral cancer patients are local recurrence at the primary site and distant metastasis. In addition, despite advancement in the treatment, the 5-year survival and overall survival rate are still lower than 50%. Therefore, understanding the underlying detailed mechanism/s of oral cancer is urgent to help to design novel therapeutic strategy. We have identified previously that the expression level of miR-455-5p is higher in tumor tissues and oral cancer cell lines than that in normal tissues and normal cell line, respectively. Inhibition of miR-455-5p decreased the anchorage-independent growth and proliferative abilities through regulating cell cycle check point proteins, suggesting miR-455-5p is an oncomiR in oral cancer tumorigenesis. By combining the array data from cancer patients and cell lines, and intersecting with the prediction results from websites to filter out possible candidates, ubiquitin conjugating enzyme 2B (UBE2B) was identified. The 3’-UTR luciferase reporter assay and western blot analysis further confirmed that UBE2B is a target gene of miR-455-5p. In soft agar colony formation assay, UBE2B suppression rescued the cell transformation ability that decreased by miR-455-5p knockdown. Microenvironmental changes and tumor hypoxia may increase the secretion of cytokines, including transforming growth factor-β (TGF-β), which has been reported to play a crucial role in premalignant and metastasis stage of oral cancer, and the link between these factors and miR-455-5p is still unclear. Our data demonstrated that TGF-β regulates miR-455-5p and UBE2B expression through the binding of Smad3 on the promoter regions. These results were further validated in animal experiments. Importantly, miR-455-5p expression was associated with the nodal status, stage, and overall survival in our patients, suggesting that miR-455-5p is a potential marker for predicting the prognosis of patients with oral cancer. In conclusion, we reveal that miR-455-5p expression is regulated by the TGF-β-dependent pathway, which subsequently leads to UBE2B down-regulation and contributes to oral cancer tumourigenesis.
論文目次 中文摘要:...... III
Abstract:..... IV
致謝...... VI
Contents: ......VII
Figure contents:......X
1. Introduction:......1
1.1. Oral cancer .....1
1.2. Transforming growth factor-β....2
1.3. Hypoxia in cancer.....2
1.4. MicroRNAs .....4
1.5. MicroRNAs functions ....5
1.6. Ubiquitin conjugating enzymes 2B...7
1.7. Epithelial mesenchymal transition ...7
2. Hypothesis and specific aims.....9
3. Materials and methods: .....10
3.1. Cell cultures and chemicals.....10
3.2. Antibodies .....10
3.3 Lentivirus particle production....11
3.4 Reverse transcription and quantitative polymerase chain reaction (qPCR)..12
3.5 Chromatin Immunoprecipitation assay (ChIP) ....13
3.6 Cell proliferation assay....14
3.7 Migration assay ....15
3.8 Western blot......15
VIII
3.9 3’-UTR luciferase reporter assay....16
3.10 Cell cycle analysis.....17
3.11 Soft agar colony formation assay....17
3.12 Animal studies ......18
3.13 Immunohistochemistry....18
3.14 Clinical samples and patient characteristics ...19
3.15 Statistical analysis ....19
4. Results:.....20
4.1 Identification of putative miRNA expression in oral tumor tissue compare to normal tissue......20
4.2 MiR-455-5p regulates anchorage-independent growth and proliferative ability. .20
4.3 UBE2B is a potential target of miR-455-5p. ....21
4.4 The clinical correlation between UBE2B and miR-455-5p ..23
4.5 MiR-455-5p regulates cancer cell growth through UBE2B ...23
4.6 MiR-455-5p regulates UBE2B in TGF-β-dependent pathway...24
4.7 Hypoxia decreases UBE2B expression by enhancing the expression of miR-455-5p 25
4.8 MiR-455-5p regulates migratory ability of oral cancer..26
4.9 MiR-455-5p effects tumor cell growth through regulating of UBE2B..27
4.10 Expression level of miR-455-5p predicts the prognosis of patients with OSCC ..28
5. Discussions:......29
5.1 MiR-455-5p was identified from oral cancer patients’ specimens ..29
5.2 MiR-455-5p is an oncomiR in oral cancer ...29
5.3 UBE2B is a novel target and modulates proliferation in miR-455-5p regulation..30
5.4 TGF-β and hypoxia induce miR-455-5p expression ...31
IX
5.5 MiR-455-5p regulates EMT and migratory ability in oral cancer ..32
6. Conclusion and future works:.....34
7. References:.....35
8. Figures and tables ......43
9. Publication:......66
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