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研究生： 蔡承翰
Tsai, Cheng-Han
論文名稱： ANGPTL4和DUSP6在調節HNSCC轉移中的功能作用
The functional role of ANGPTL4 and DUSP6 in the regulation of HNSCC metastasis
指導教授： 陳炳焜
Chen, Ben-Kuen
學位類別： 碩士
Master
系所名稱： 醫學院 - 藥理學研究所
Department of Pharmacology
論文出版年： 2020
畢業學年度： 108
語文別： 中文
論文頁數： 69
中文關鍵詞： 頭頸癌 、雙重特異性磷酸酶6 、癌症轉移
外文關鍵詞： head and neck cancer, DUSP6, metastasis
相關次數： 點閱：84  下載：0 
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    • 雙重特異性磷酸酶6 ( Dual specificity phosphatase 6, DUSP6)，在先前的文獻中指出是一個位在細胞質並具有p-ERK特異性結合的絲裂原活化激酶的負調節者，會透過p-ERK的途徑被誘導，在反過來抑制p-ERK的活化，並擁有著不同的角色，可扮演著腫瘤促進者或腫瘤抑制者。另外，在頭頸鱗狀細胞癌大約80%的患者都會有EGFR過度表達的情形，並有著與EGF特異性結合活化p-ERK的途徑。因此也表示DUSP6在其中可能扮演重要的角色，然而，DUSP6在頭頸鱗狀細胞癌(Head and neck squamous　cell carcinoma, HNSCC)中的角色尚未被釐清。在本研究中，發現EGF在HNSCC會高度誘導DUSP6的表達，並再次確認了DUSP6會透過p-ERK的途徑被誘導，而不會透過N F  B途徑。此外，亦發現 DUSP6 在這之中 扮演著腫瘤促進者，並在將DUSP6敲除後，不僅會降低頭頸鱗狀細胞癌的爬行，還會減少腫瘤抗失巢凋亡(anoikis resistance)的能力，甚至會增加化療藥物的敏感性，藉此增加細胞凋亡。整體來說，本研究顯示DUSP6在HNSCC中扮演著腫瘤促進者的角色，在未來可能具有治療發展上面的潛力。

    Dual specificity phosphatase 6 (DUSP6), which was pointed out in the previous literature as a negative regulator of mitogen-activated kinase that is located in the cytoplasm and has specific binding to p-ERK, passes through p-ERK. The pathway is induced, which in turn inhibits the activation of p-ERK, and has a different role, can act as a tumor promoter or tumor suppressor. In addition, about 80% of patients with head and neck squamous cell carcinoma overexpress EGFR, and there is a well-known pathway that specifically binds to EGF to activate p-ERK. Therefore, it also indicates that DUSP6 may play an important role in it, however, the role of DUSP6 in head and neck squamous cell carcinoma (HNSCC) has not yet been clarified. In this study, EGF was found to highly induce DUSP6 expression in HNSCC, and it was confirmed again that DUSP6 would be induced through the p-ERK pathway instead of the NF-B pathway. In addition, it has also been found that DUSP6 plays a role as a tumor promoter, and after knocking down DUSP6, it will not only reduce the crawling of squamous cell carcinoma of the head and neck, but also reduce the ability of the tumor to resist anoikis. It may even increase the sensitivity of chemotherapeutic drugs, thereby increasing apoptosis. Overall, this study shows that DUSP6 plays the role of a tumor promoter in HNSCC and may have potential for therapeutic development in the future.

    目錄 中文摘要………………………………………………………………… Ⅰ 英文摘要………………………………………………………………… Ⅱ 誌謝……………………………………………………………………… Ⅳ 目錄……………………………………………………………………… Ⅵ 表目錄…………………………………………………………………… Ⅸ 圖目錄…………………………………………………………………… Ⅹ 縮寫表…………………………………………………………………… Ⅺ 一、研究背景……………………………………………………………… 1 1-1 頭頸鱗狀細胞癌………………………………………………… 1 1-2 頭頸癌和表皮生長因子的關聯性……………………………… 3 1-3 發炎促進頭頸癌的進程………………………………………… 5 1-4 血管生成素樣-4………………………………………………… 6 1-5 雙重特異性磷酸酶6 簡介……………………………………… 7 1-6 研究目的………………………………………………………… 11 二、材料與方法…………………………………………………………… 13 2-1 細胞株培養……………………………………………………… 13 2-2 RNA 萃取………………………………………………………… 13 2-3 反轉錄反應……………………………………………………… 14 2-4 即時定量聚合酶連鎖反應……………………………………… 14 2-5 全細胞裂解……………………………………………………… 15 2-6 西方墨點法……………………………………………………… 15 2-7 短暫性基因致弱實驗…………………………………………… 16 2-8 NF-B 與ERK 抑制實驗 ………………………………………… 16 2-9 抗失巢凋亡實驗………………………………………………… 17 2-10 細胞遷移實驗 ………………………………………………… 17 2-11 報導基因轉染實驗 …………………………………………… 18 2-12 細胞黏附實驗 ………………………………………………… 19 三、實驗結果 ………………………………………………………………20 3-1 PGE2 和EGF 誘導ANGPTL4 mRNA 的表達 ……………………… 20 3-2 PGE2所誘導的ANGPTL4 不透過PPAR-的路徑………………… 20 3-3 PGE2 聯合EGF 不會更促進細胞的爬行………………………… 21 3-4 PGE2 會增進細胞與細胞間的黏附……………………………… 22 3-5 PGE2 不會誘導DUSP6 的表達…………………………………… 22 3-6 EGF 所誘導的DUSP6 並不會調控到ANGPTL4 的表達………… 23 3-7 在低濃度的EGF 處理時, DUSP6 的表達量就到達上限……… 24 3-8 敲除DUSP6 會降低細胞侵襲的能力…………………………… 25 3-9 敲除DUSP6 增進細胞的失巢凋亡……………………………… 26 3-10 EGF 所誘導的DUSP6 是透過p-ERK 的途徑,而不是NF-B… 27 四、討論 ……………………………………………………………………28 4-1 PGE2聯合EGF 對FaDu 細胞的功能影響………………………… 28 4-2 DUSP6 在HNSCC 中的功能與角色 ……………………………… 29 4-3 未來研究方向 …………………………………………………… 32 參考文獻…………………………………………………………………… 34 圖表………………………………………………………………………… 42 表目錄 表一、反轉錄世紀反應物 ………………………………………………… 43 表二、即時定量聚合酶連鎖反應用引子序列與黏合溫度 ……………… 44 表三、西方墨點法使用之抗體 …………………………………………… 45 圖目錄 圖一、PGE2 和EGF 誘導ANGPTL4 mRNA 的表達…………………………… 46 圖二、PGE2所誘導的ANGPTL4 不透過PPAR-的路徑 ………………… 47 圖三、PGE2聯合EGF 不會更促進細胞的爬行…………………………… 48 圖四、PGE2 會增進細胞與細胞間的黏附 ………………………………… 50 圖五、PGE2不會誘導DUSP6 的表達……………………………………… 52 圖六、EGF 所誘導的DUSP6 並不會調控到ANGPTL4 的表達…………… 53 圖七、在低濃度的EGF 處理時, DUSP6 的表達量就到達上限………… 57 圖八、敲除DUSP6 會降低細胞侵襲的能力……………………………… 59 圖九、敲除DUSP6 增進細胞的失巢凋亡 ………………………………… 64 圖十、EGF 所誘導的DUSP6 是透過p-ERK 的途徑,而不是NF-B……… 67 圖十一、敲除DUSP6 會降低細胞的生存能力………………………………69

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