Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/51973
標題: Molecular mechanisms of resveratrol and its analogs, active compounds of ginger and citrus on the suppression of invasion and metastasis in human hepatocarcinoma cells
白藜蘆醇及其衍生物、薑及柑橘活性成分抑制人類肝癌細胞侵入與轉移作用及其分子機轉之研究
作者: Wu, Cheng-Feng
吳承峰
關鍵字: resveratrol;薑酚;gingerol;citrus;hepatocarcinoma;invasion;metastasis;matrix metalloproteinase;柑橘;肝癌;侵入;轉移;基質金屬蛋白酶
出版社: 食品暨應用生物科技學系所
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R. and Kensler, T. W. 19
摘要: 
紅酒多酚白藜蘆醇 [3,5,4’-trihydroxystilbene (resveratrol)] 及其衍生物 [3,5,4’-trimethoxy-trans-stilbene (MR-3), 3,4,3’,4’,5’,- pentamethoxystilbene (MR-5) 與 trans-3,5-dimethoxy-4’- hydroxystilbene (pterostilbene)],薑活性成分之薑酚 (6-gingerol) 與薑烯酚 (6-shogaol),以及柑橘屬水果成分之多甲氧基類黃酮化合物 [5,6,7,8,3’,4’-hexamethoxy flavone (nobiletin) 與 5-hydroxy-3,6,7,8,3’,4’- hexamethoxyflavone (5-OH-HxMF)] 同屬存在於植物中之多酚類化合物,具有抗氧化、抗發炎、抗癌與抑制細胞黏附等活性,於動物試驗已證實具有抑制腫瘤形成、發展及轉移的能力。因此,本研究目的為探討白藜蘆醇及其甲基化衍生物、薑與柑橘活性成分在 HepG2 與 Hep3B 兩種肝癌細胞模式中,對其侵入與轉移之抑制效應及其可能之作用機轉。
研究結果顯示:(1) HepG2 細胞在不具細胞毒性 (cell viability > 80%) 之樣品作用劑量 (resveratrol, MR-3 與 6-gingerol:≦ 50 µM;6-shogaol:≦ 10 µM) 下,resveratrol、MR-3、6-shogaol 與 6-gingerol 對於 phorbol-12-myristate-13-acetate (PMA, 200 nM) 所誘發的 matrix metalloproteinase-9 (MMP-9) 酵素活性與基因表現以及細胞移行侵入能力呈現顯著的抑制效應 (P < 0.05)。而 6-shogaol (10 µM) 或 6-gingerol (50 µM) 共培養下,可抑制 HepG2 細胞 30% 之MMP-2 酵素活性;此外,resveratrol 與 MR-3 亦可顯著促進基質金屬蛋白酶之內生性抑制蛋白 tissue inhibitor of metalloproteinase-1/2 (TIMP-1/2) 基因表現;(2) 在具有 HBV 病毒染色體與缺乏 p53 基因使侵入轉移活性較佳之 Hep3B 細胞模式下,resveratrol (≦ 50 µM)、MR-3 (≦ 2.5 µM)、6-shogaol (≦ 10 µM) 與 6-gingerol (≦ 50 µM) 可隨著添加劑量增加顯著地抑制MMP-9/2 酵素活性、基因表現及細胞移行侵入能力 (P < 0.05),並更有效提升 TIMP-1/2 基因表現。此外,6-shogaol 亦可透過調控 urokinase-type plasminogen activator (uPA) 酵素活性,以抑制 MMP-9 的活化。抗氧化性分析結果顯示,上述多酚類化合物之抗侵入/轉移效應可能與其清除自由基生成能力或胞內抗氧化活性間呈正相關。然而,柑橘屬活性成分在抑制肝癌細胞侵入與轉移方面則不具顯著功效 ( P > 0.05)。
綜合上述,resveratrol、MR-3、6-shogaol 與 6-gingerol 對於肝癌細胞 MMP-9/2 酵素活性之抑制可能透過:(1) 直接對該目標基因轉錄層級之調控;(2) 透過活化TIMP-1/2 基因表現與抑制 uPA 酵素活性,間接影響 MMPs 酵素活化等作用途徑,進而抑制肝癌細胞侵入與轉移。本研究經細胞模式結果顯示,白藜蘆醇及其衍生物與薑活性成分具有抑制肝癌侵入與轉移之功效。本研究成果有助於了解白藜蘆醇及其衍生物與薑活性成分於抗肝癌活性上之保健功效,亦可提供未來開發相關機能性產品之重要參考。

Resveratrol (3,5,4'-trihydroxystilbene) and its analogs including 3,5,4'-trimethoxy-trans-stilbene (MR-3), 3,4,3',4',5',- pentamethoxystilbene (MR-5) and trans-3,5-dimethoxy-4'- hydroxystilbene (pterostilbene) from red wine, 6-shogaol and 6-gingerol from active compounds of ginger and 5,6,7,8,3',4'-hexamethoxy flavone (nobiletin) and 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF) from polymethoxyflavone of citrus fruits are common phytochemical components. The antioxidative, anti-inflammatory, anti-cancer and cell adhesion inhibitory activities of these phytochemical components have been studied and reported in the literatures. Additionally, the potential suppressive effects on cancer cell initiation, progression and metastasis have been verified in vivo. In the present study, the anti-invasive and anti-metastatic effects of resveratrol and its analogs and the active compounds of ginger and citrus on human hepatocarcinoma cells (HepG2 and Hep3B cells) were investigated to clarify the underlying mechanisms.
The findings in this studies revealed : (1) In the HepG2 cell model, treatment with resveratrol (≦ 50 µM), MR-3 (≦ 50 µM), 6-shogaol (≦ 10 µM) and 6-gingerol (≦ 50 µM) in the presence of 200 nM phorbol-12- myristate-13-acetate (PMA) for 24 h significantly (P < 0.05) inhibitied PMA-induced invasion and matrix metalloproteinase-9 (MMP-9) activity and messenger RNA levels without increased cytotoxicity. In addition, MMP-2 activity was reduced to 70 % compared with the PMA treatment only by treatment with 6-shogaol and 6-gingerol at concentrations of 10 and 50 µM, respectively. Moreover, treatment with resveratrol and MR-3 increased the expression of tissue inhibitor of metalloproteinase-1/2 (TIMP-1/2); (2) In Hep3B, the hepatitis B virus (HBV)-DNA-containing and p53 gene inactivation hepatocarcinoma cell line that is highly invasive and has increased metastatic capability, resveratrol (≦ 50 µM), MR-3 (≦ 2.5 µM), 6-shogaol (≦ 10 µM) and 6-gingerol (≦ 50 µM) also exhibited a significant (P < 0.05) inhibitory effect on invasion and MMP-9/2 activities and messenger RNA levels in a dose-dependent manner. Contrarily, the expression of TIMP-1/2 in cells was up-regulated by treatment with these compounds. Additionally, the activity of urokinase-type plasminogen activator (uPA), which is involved in the activation of MMP-9, was down-regulated by treatment with 6-shogaol. Compared to the antioxidative activities of these polyphenol compounds, it was found that the anti-invasive and anti-metastatic effects correlated to their cellular antioxidant activities and inhibitory effect on the production of reactive oxygen species. The active compounds of citrus, nobiletin and 5-OH-HxMF, may not the anti-invasive and anti-metastatic compounds.
In summary, resveratrol, MR-3, 6-shogaol and 6-gingerol inhibited the MMP-9/2 activity of human hepatocarcinoma cells through directly regulating the transcriptional level, increasing the expressions of TIMP-1/2 and inhibiting the uPA activity. The invasion and metastasis of human hepatocarcinoma cells might be further inhibited by decreasing the MMP-9/2 expression in cells. These results provide evidence for the anti-invasive effects of resveratrol and its analogs, and the active compounds of ginger on hepatoma cells and may lead to the development of high-value health food in the future.
URI: http://hdl.handle.net/11455/51973
Appears in Collections:食品暨應用生物科技學系

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