口腔鱗狀上皮細胞癌（oral squamous cell carcinoma, OSCC）是一種具有高度侵略性的口腔惡性腫瘤。根據世界衛生組織的統計，每年大約有50萬人罹患OSCC。隨著發病率和死亡率的增加，這一全球性的健康問題更顯突出。在包括台灣在內的南亞中，口腔癌和口咽癌是常見發生形式。此外，口腔內癌症的患病率正在上升，尤其是在年輕的男性人群中。這可能歸因於一些危險因子，例如吸煙、咀嚼檳榔和飲酒。並且，遺傳和表觀遺傳學也對OSCC癌變有很大的影響。
目前為止，許多的證據表明由於賴氨酸去甲基酶4（KDM4AE）能夠催化從H3的3/2甲基化賴氨酸9/36中去除甲基的這一過程，因此KDM4AE在癌症進展以及腫瘤轉移中起著重要作用。王教授的實驗室先前已經確定了KDM4B的結構並確定了有效的抑制劑。因此在這項研究中，我使用KDM4抑制劑並藉由細胞株和斑馬魚模型來研究其在OSCC進展中的抑制作用。我們發現抑制劑可以有效抑制OSCC存活並降低OSCC細胞的KDM4去甲基能力。並且抑制劑可顯著降低OSCC細胞遷移能力，而不會威脅斑馬魚的生命和發育。這些結果表明，KDM4抑制劑可以在體內和體外抑制OSCC細胞的增殖能力和遷移能力。因此，抑制KDM4提供了一種治療OSCC的新策略。

Oral squamous cell carcinoma（OSCC）is a kind of oral cavity malignancy with highly aggressive ability. According to the World Health Organization, approximately 500,000 people are estimated to have OSCC. This global health problem is even more noted with increasing incidence and mortality rates. Oral and pharyngeal cancers are a common form in South Asia including Taiwan. The prevalence of intra-oral cancer is noted to be rising, especially in younger, male population. This may be attributed to risk factors, such as tobacco-using, betel nut-chewing, and alcohol. Genetic inheritance and epigenetics also have great impacts on OSCC carcinogenesis.
Accumulated evidence shows that lysine demethylase 4 (KDM4AE) that catalyzes the removal of the methyl group(s) from tri/dimethylated lysine 9/36 of H3 plays an important role in cancer progression and tumor metastasis. Professor’s Wang’s lab has previously determined the structure of KDM4B and identified potent inhibitors. In this study, I used the KDM4 inhibitors to investigate the inhibitory effects of OSCC progression using cell lines and the zebrafish model. We showed that the inhibitors could effectively suppress the OSCC survival and decrease the KDM4 demethylation ability of OSCC cells. The inhibitors could significantly decrease the OSCC cell migration ability without threatening the life and development of zebrafish. These results suggested that KDM4 inhibitors could suppress the proliferation ability and the migration ability of OSCC cells in vivo and in vitro. KDM4 inhibition thus provides a new intervention strategy to treat OSCC.

中文摘要 3
Abstract 4
縮寫列表 6
緒言 11
實驗方法與材料 20
實驗結果 27
結果與討論 33
參考資料 37
Figures 41
附錄 61

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