褪黑激素抑制口腔癌細胞轉移之機制探討

Study of the inhibitory effects of melatonin on the metastasis of oral cancer cells

葉家銘

褪黑激素 ； 轉錄輔助活化因子 ； 組織蛋白乙醯化 ； 基質金屬蛋白水解酶 ； melatonin ； CREBBP ； EP300 ； Histone acetylation ； matrix metalloproteinase

中山醫學大學醫學研究所學位論文

2016年

博士

楊順發

繁體中文

口腔癌是發生在口腔部位之惡性腫瘤的總稱，可出現在口腔的任何部位，而且口腔癌每年在男性的死亡人口有迅速增加的趨勢。造成口腔癌的死亡原因主要在於癌症的轉移 (metastasis)。儘管醫療技術日新月異的進步，但口腔癌在世界各地的五年內死亡率仍有 50%。褪黑激素 (melatonin) 是人體中分泌的一種賀爾蒙，具有調節生理時鐘、時差及幫助睡眠等作用。有許多文獻指出，褪黑激素也具有抗氧化及抗腫瘤等功效，但目前對於褪黑激素抑制口腔癌細胞轉移與侵襲之能力及其詳細機轉仍不清楚。因此，在此研究中主要探討褪黑激素對於口腔癌細胞侵襲轉移之影響及其調控路徑。在此實驗中，我們發現褪黑激素可以減少由 12-O-tetradecanoylphorbol-13-acetate (TPA) 所誘導的口腔癌細胞 HSC-3 及 OECM-1 的轉移能力。利用 Gelatin zymography assay、Quantitative real-time PCR 及 Western blot 發現褪黑激素能減少基質金屬蛋白水解酶-9 (matrix metalloproteinase-9, MMP-9) 的活性及其 mRNA 與蛋白的表現量。此外，由免疫沉澱法與染色質免疫沉澱法實驗結果發現褪黑激素抑制 Extracellular signal-regulated kinase 1/2 之磷酸化而影響下游轉錄輔助因子如CREBBP、EP300 的表現量，導致口腔癌細胞組織蛋白乙醯化的減少，進而阻斷 MMP-9 mRNA 的轉錄。最後由臨床檢體的分析結果發現在口腔癌組織中其 MMP-9、CREBBP 及 EP300 相較於正常組織中有明顯增加之趨勢。另外，CREBBP 與 MMP-9、EP300 表現量之相關性也呈現正相關的趨勢。總結本實驗之結果，我們發現褪黑激素抑制口腔癌細胞 HSC-3 及 OECM-1 之移行透過減少組蛋白乙醯化影響 MMP-9 之表現與活性的分子機制。

Melatonin exerts antimetastatic effects on liver and breast cancer and also inhibits matrix metalloproteinase (MMP) activity. However, the detailed impacts and underlying mechanisms of melatonin on oral cancer cell metastasis are still unclear. This study showed that melatonin attenuated the 12-O-tetradecanoylphorbol-13-acetate-induced migration of oral cancer cell lines, HSC-3 and OECM-1. Zymography, quantitative real-time PCR, and Western blotting analyses revealed that melatonin lessened MMP-9 enzyme activity as well as the expression of MMP-9 mRNA and protein. Furthermore, melatonin suppressed the phosphorylation of the ERK1/2 signalling pathway, which dampened MMP-9 gene transcription by affecting the expression of transcriptional coactivators, such as CREB-binding protein (CREBBP) and E1A binding protein p300 (EP300), and decreasing histone acetylation in HSC-3 and OECM-1 cells. Examinations on clinical samples exhibited that MMP-9, CREBBP, and EP300 were significantly increased in oral cancer tissues. Moreover, the relative level of CREBBP was positively correlated with the expression of MMP-9 and EP300. In conclusion, we demonstrated that melatonin inhibits the motility of HSC-3 and OECM-1 cells in vitro through a molecular mechanism that involves attenuation of MMP-9 expression and activity mediated by decreased histone acetylation.

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