褪黑激素抑制人類鼻咽癌細胞轉移及侵襲機制探討

Study of the inhibitory effects and molecular mechanisms of melatonin on the cell migration and invasion of nasopharyngeal carcinoma

何心妤(Hsin-Yu Ho)

指導教授 ： 楊順發

中山醫學大學/醫學院/醫學研究所/博士(2017年)

摘要

鼻咽癌在頭頸癌中屬於具有高度淋巴結轉移的癌症，好發於東南亞地區。褪黑激素是一種內生性激素，存在於動物、植物、黴菌及細菌中，在動物體內主要是由松果體所分泌。褪黑激素目前已知可能透過多種機制來抑制癌症生長或轉移，但其中的分子機制還需研究分析。本篇研究指出，在鼻咽癌細胞中，褪黑激素能夠透過調降基質金屬蛋白酶 (matrix metalloproteinases，MMPs)中的MMP-9來抑制由12-O-tetradecanoylphorbol-13 acetate (TPA)所誘發的細胞轉移。其中，褪黑激素經由影響轉錄因子specificity protein-1 (SP-1)蛋白表現量，進而使MMP-9 mRNA表現量下降。分析其路徑發現，褪黑激素透過MMP-9上游c-Jun N-terminal kinase (JNK)訊息傳遞路徑，影響細胞的侵襲及轉移。綜合以上結果證實，褪黑激素透過抑制轉錄因子SP-1表現量及SP-1與MMP-9 DNA的結合能力，影響由TPA所誘發的MMP-9表現量，並降低鼻咽癌細胞株侵襲及轉移能力。研究首次發現褪黑激素對鼻咽癌細胞的作用機制，此一發現對於鼻咽癌細胞抗轉移的機制又更加深入，褪黑激素對未來在鼻咽癌的治療可能是一個極具潛力的輔助藥物。

關鍵字

褪黑激素 ； 基質金屬蛋白酶-9 ； 癌轉移

並列摘要

Nasopharyngeal carcinoma (NPC), a disease common in the South-East Asian population, has high lymph node metastatic ability. Melatonin, an endogenously produced substance present in animals, plants, fungi, and bacteria, has oncostatic activity via several mechanisms. The molecular mechanisms involved in melatonin-mediated tumor inhibitory potential are not completely defined. Here, we show that melatonin treatment inhibits TPA-induced cell motility by regulating the matrix metalloproteinase-9 (MMP-9) expression in NPC. We also identified the signaling cascade through which melatonin inhibits MMP-9 expression; this involves melatonin regulating the binding activity of the transcription factor specificity protein-1 (SP-1)-DNA. Our mechanistic analysis further reveals that the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway is involved in the melatonin-mediated tumor suppressor activity. Furthermore, the findings indicate a functional link between melatonin-mediated MMP-9 regulation and tumor suppressing ability and provide new insights into the role of melatonin-induced molecular regulation of tumor invasion. Thus, we conclude that melatonin suppresses the motility of NPC by regulating TPA-induced MMP-9 gene expression via inhibiting SP-1-DNA binding ability. The results provide a functional link between melatonin-mediated SP-1 regulation and the antimetastatic actions of melatonin on nasopharyngeal carcinoma.

並列關鍵字

Melatonin ； MMP-9 ； Tumor invasion

參考文獻

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