卷柏萃取物抑制人類鼻咽癌細胞轉移和侵襲之機制探討

Study of the inhibitory effects of Selaginella tamariscina extract on metastasis and invasion of nasopharyngeal carcinoma

10.6834/CSMU.2012.00062

何心妤

鼻咽癌 ； 卷柏 ； MMP-9 ； 癌轉移 ； Nasopharyngeal carcinoma ； Selaginella tamariscina ； matrix metalloproteinase-9 ； cancer metastasis

中山醫學大學醫學研究所學位論文

2012年

碩士

楊順發

繁體中文

鼻咽癌是一種發生在頭頸部的癌症，好發於東亞地區，其中男性發生率比女性高三倍，而造成鼻咽癌病患死亡的主因則是癌轉移。在癌症轉移中，腫瘤會釋出趨化因子、生長因子及基質金屬蛋白酶 (Matrix metalloproteinase, MMP)，分解細胞外基質(extracellular matrix, ECM)，形成血管新生，並藉由血液流動，轉移到其他組織。卷柏 (Selaginella tamariscina)是常見的中草藥，用於治療出血、慢性肝炎，近年來更有研究指出卷柏具有抗癌效果，但對於鼻咽癌的抗癌機制尚未釐清。因此本篇研究將探討卷柏在鼻咽癌轉移中所扮演的角色及詳細機制為何。12-O-tetradecanoyl-phorbol-13-acetate (TPA)是一種腫瘤促進因子，可使癌細胞株更趨近於人體內腫瘤起始狀態，研究指出，TPA會誘發腫瘤細胞的MMP-9，使細胞轉移更為明顯。首先，我們在gelatin zymography assay中發現卷柏萃取物在鼻咽癌細胞HONE-1中會抑制由TPA所誘發的MMP-9蛋白活性。接著我們在Boyden chamber assay中觀察到卷柏萃取物明顯抑制由TPA所誘發HONE-1的侵襲及轉移能力。因此我們推測，卷柏萃取物可能藉由調控MMP-9的基因活性來抑制癌咽癌細胞的轉移及侵襲。我們進一步以reverse-transcription PCR及real-time PCR發現卷柏萃取物明顯抑制由TPA所誘發的MMP-9 mRNA表現。並且在luciferase assay中發現MMP-9啟動子活性確實受到卷柏萃取物的抑制。另外在訊息傳遞路徑部分，我們發現TPA對HONE-1中MMP-9活性的調控是經由ERK、p38及PKC路徑。總結以上結果，我們發現在鼻咽癌細胞HONE-1中，卷柏萃取物可能透過抑制TPA所誘發的MMP-9表現使癌轉移能力降低，但其上游訊息傳遞路徑還有待進一步實驗證實。除此之外，卷柏萃取物對MMP-9 轉錄因子的調控，也需要以ChIP assay來找出詳細的調控機制。

Nasopharyngeal carcinoma (NPC), a cancer occurring in head and neck, has the highest incidence in the East Asian region, while the incidence of males is three times higher than that of females. During cancer metastasis, the extracellular matrix (ECM) was decomposed by releasing of chemokines, growth factors and matrix metalloproteinases (MMPs), followed by angiogenesis formation through the blood flow, and then transferring to other organs. Since metastasis is the leading cause of death for NPC, resolving or prevention for metastasis is vital for the clinical management of NPC. Selaginella tamariscina is a widely used chinese herbal medicine for bleeding and chronic hepatitis. Previous researches showed that Selaginella tamariscina has anti-cancer effects without a clearly defined molecular mechanism. 12-O-tetradecanoyl -phorbol-13-acetate (TPA) is a tumor promoter and may lead cancer cell lines to be more like to that the beginning in the human body. In this study, we found that Selaginella tamariscina extract (STE) suppresses TPA-induced matrix metalloproteinase-9 (MMP-9) expression in nasopharyngeal carcinoma cell line HONE-1. The STE also inhibits TPA-induced metastasis and invasion, as shown by results of the Boyden chamber assay. Therefore, we hypothesized that the STE may inhibit TPA-induced metastasis and invasion through the regulation of MMP-9 gene activity. Furthermore, results from reverse-transcription PCR/ real-time PCR and luciferase assay indicated that STE significantly inhibits TPA-induced MMP-9 mRNA expression and the promoter activity of MMP-9. Meanwhile, our results also revealed that TPA may regulate MMP-9 activity by ERK, p38, and PKC pathway in HONE-1 cell line. In conclusion, STE may inhibit TPA-induced metastasis and invasion through MMP-9 in nasopharyngeal carcinoma cell line HONE-1 and the signaling pathway and the regulatory of MMP-9 transcription factor remains to be confirmed in the future work.

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