臺灣博碩士論文加值系統

根據世界衛生組織資料顯示口腔癌為全球盛行率第八的癌症。而在國內衛生署統計男性十大癌症排行中，口腔癌位居第四，其發生率更是節節攀升。因此口腔癌相關的致癌因子研究更顯得重要。MicroRNAs (miRNAs)為內生性非編碼的小片段序列，作用為負向調控其目標基因，miRNA的突變和異常表現與口腔癌有密切的相關。
先前本實驗室發現miR-372在口腔癌臨床組織中有較高的表現，而在本研究中發現miR-372會促進口腔癌細胞株的移行能力。透過預測軟體分析以及西方點墨法、qRT-PCR找到miR-372的新目標基因p62，進而發現miR-372 透過抑制p62促進口腔癌細胞株的移行、侵襲及非貼附性生長能力。NQO1為Nrf2 轉錄因子抗氧化機轉下游重要的phase Ⅱ酵素，在本研究中發現miR-372-p62分子路徑可調控NQO1的表現，影響口腔癌細胞株的活性氧化物質(ROS)的平衡，這些活性氧化物質的累積會增加細胞的移行能力。缺氧為誘導癌症侵襲性之重要因素，本研究探討miR-372訊息軸是否受到缺氧環境的調控，結果顯示在低氧環境培養下，miR-372表現量明顯上升，p62和NQO1的表現量則隨著培養時間而下降。過去文獻指出miRNA可做為評估預後的重要指標，本研究在口腔癌臨床組織中亦證實miR-372-p62-NQO1訊息軸的調控，而miR-372在血液以及唾液中的表現，可能為口腔癌較差的預後指標。
本研究亦探索miR-372是否能經由其他路徑調控口腔癌的進展。由生物訊息分析發現miR-372和ZBTB7A呈負相關且在口腔癌細胞株中降低ZBTB7A的表現。雖然ZBTB7A在各種癌症中角色不一，在口腔癌細胞中ZBTB7A的表現抑制細胞移行、侵襲和及非貼覆性生長能力，同時促進細胞凋亡產生。由上述結果得知miR-372參與多種口腔癌癌化過程調控，透過標靶p62和ZBTB7A促進口腔癌癌化的病程。

According to the survey of WHO oral carcinoma is ranked the eighth leading malignancy in the world cancer. In Taiwan, it ranks fourth at the male top ten cancers. The incidence rate is increasing year by year. Therefore, the investigation of oral carcinoma demands immediate attention. MicroRNAs are small non-coding RNAs functioning by repressing target genes. It has been reported that the mutation and aberrant expression of miRNAs are closely related to oral tumorigenesis.
The previous study in our laboratory found that miR-372 was highly expressed in oral squamous cell carcinoma (OSCC) tissues. In this study we found that miR-372 increased the OSCC cell migration. By using in silico platform, western blot analysis, qRT-PCR assay we found that p62 (Sequestosome 1) was the new target gene of miR-372. miR-372 promoted cell migration, invasion, anchorage-independent growth of OSCC cells. NQO1 is a downstream major phase Ⅱ enzyme of Nrf2 antioxidant mechanism. Our results showed that miR-372-p62 axis modulated NQO1 expression, which further altered the balance of ROS level in cells. The accumulation of ROS increased the capability of cell migrations. Hypoxia has significant role in promoting cancer invasion. We identified that miR-372 axis was regulated by hypoxia as miR-372 expression was increased, and the expression of p62 and NQO1 were decreased in accordance with hypoxic time course. miRNAs have been reported as good prognosis markers in cancer. Our results confirmed the miR-372-p62-NQO1 regulation in OSCC tissues. In addition, the level of miR-372 in plasma and saliva might be the poor prognosis marker in OSCC.
To discover the novel miR-372 related target, we searched biological database and found that ZBTB7A expression was opposite to miR-372expression. Although ZBTB7A has different roles in various cancers, our analysis showed that miR-372 repressed ZBTB7A expression in OSCC cells. Overexpression of ZBTB7A in OSCC cells decreased the abilities of cell migration, invasion and anchorage-independent growth and increased the apoptosis of OSCC cells. The study concludes that miR-372 modulates crucial signaling pathways associated with OSCC pathogenesis by targeting p62 and ZBTB7A.

中文摘要........................................I
Abstract........................................II
目錄............................................III
I.緒論(Introduction)...........................1
1.1口腔癌(Oral Carcinoma)......................1
1.2微型RNA(MicroRNA，miRNA)........................2
1.3缺氧調控(Hypoxia).......................3
1.4 miR-372和癌症..........................4
1.5 p62 (Sequestosome-1, SQSTM1)....................5
1.6 Zinc finger and BTB domain containing 7 (ZBTB7A)....6
II. 研究動機與目標(Purpose)..................8
2.1 研究動機................................8
2.2 研究目標.........................8
III. 材料與方法(Materials and Methods)............9
3.1 細胞培養................................9
3.2 試劑....................................9
3.3 細胞表現型.............................9
3.4 報導基因質體建構和活性分析(Reporter construct and activity assays)........................12
3.5 組織和血液樣本.......................12
3.6 穩定表現細胞株之建立....................13
3.7 即時聚合酶鏈鎖反應 (Quantitative (q)RT-PCR).....14
3.8 西方墨點法(Western blot analysis)............14
3.9 免疫染色...........................14
3.10 ROS 偵測......................15
3.11 動物實驗....................15
3.12 細胞週期測定.....................15
3.13 統計分析 (Statistical analysis)..............16
IV. 實驗結果(Result)....................17
4.1 miR-372在口腔癌細胞中之表現和功能.............17
4.2 miR-372在口腔癌細胞中的新目標基因..............17
4.3 p62在口腔癌細胞中的表現與功能................18
4.4 p62在口腔癌細胞中的下游路徑.................19
4.5 miR-372和p62參與ROS的調控.................20
4.6 缺氧調控透過miR-372-p62-NQO1訊息軸調控細胞移行能力....21
4.7 miR-372和p62在口腔癌組織中的表現............23
4.8 miR-372在口腔癌細胞中其他的新目標基因...........25
4.9 ZBTB7A 在口腔癌細胞中的功能.................26
V. 討論(Discussion).......................30
VI. 圖列(Figures)............................36
圖一、miR-372在口腔癌細胞高表現且促進口腔癌細胞移行能力...36
圖二、miR-372對口腔癌細胞之增生能力沒有影響........37
圖三、miR-372抑制p62 mRNA和蛋白質表現...............38
圖四、miR-372直接作用於p62 mRNA 3’UTR.............39
圖五、口腔癌細胞中p62的表現量較正常上皮細胞低.........40
圖六、細胞中抑制p62促進細胞之移行能力..............41
圖七、穩定表現和抑制p62之細胞株對細胞移行能力的影響....42
圖八、p62能回復miR-372造成之惡性表現型............43
圖九、p62和NQO1表現量和表現位置相關...............44
圖十、NQO1對細胞移行能力之影響.................45
圖十一、miR-372-p62-NQO1訊息軸對ROS的影響.........46
圖十二、NAC有效減低細胞爬行能力................47
圖十三、缺氧環境對於口腔癌細胞中miRNAs之影響......48
圖十四、缺氧情形調控miR-372-p62-NQO1訊息軸.........49
圖十五、缺氧情形調控miR-372-p62-NQO1訊息軸(NQO1處理)......50
圖十六、缺氧情形調控miR-372-p62-NQO1訊息軸(多重處理).....51
圖十七、p62有效降低缺氧調控造成之細胞移行能力上升..........52
圖十八、p62不影響腫瘤生長..................53
圖十九、p62於組織中的表現........................54
圖二十、臨床組織中miR-372-p62-NQO1之表現.............55
圖二十一、口腔癌病人唾液和血漿中miR-372之表現.........56
圖二十二、ZBTB7A於口腔角質細胞之表現.............57
圖二十三、miR-372抑制ZBTB7A表現...............58
圖二十四、miR-372抑制ZBTB7A表現..............59
圖二十五、ZBTB7A 為miR-372之新目標基因...........60
圖二十六、刪減ZBTB7A表現增加細胞移行能力..........61
圖二十七、ZBTB7A穩定抑制和過度表達細胞株之建立........62
圖二十八、ZBTB7A在SAS口腔癌細胞株中之功能........63
圖二十九、刪減ZBTB7A增加細胞增生能力..............64
圖三十、ZBTB7A對於細胞週期之影響..............65
圖三十一、ZBTB7A對於Cisplatin、Taxol處理之SAS、FaDu細胞存活度之影響.............................66
圖三十二、ZBTB7A對於細胞凋亡之影響..............67
圖三十三、ZBTB7A對於細胞凋亡訊息之調控...........68
VII. 表列(Tables)..................69
Table 1.本研究中使用之小分子干擾核糖核酸(siRNA)....69
Table 2. 臨床口腔癌檢體組織...................70
Table 3. sh-RNA和本研究使用之穩定刪減和過表現質體........71
Table 4. 本研究使用之抗體(上；初級抗體，下；次級抗體).....72
VIII. 附圖(Supplementary Figures).....................73
附圖一、找尋miR-372新目標基因示意圖......................73
附圖二、以starbase分析ZBTB7A在不同癌症中表現之情形，HNSCC為頭頸鱗狀細胞癌............................................74
附圖三、以starbase分析口腔癌，ZBTB7A和miR-372表現呈負相關.75
IX. 參考文獻(References)..............................76

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