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標題: 薑活性成分抑制人類肝癌細胞侵入及轉移作用分子機轉之研究
Molecular mechanisms of active compounds of ginger on the suppressions of invasion and metastasis in human hepatocarcinoma cells
作者: Chou, Chai-Ping
關鍵字: 6-gingerol
matrix metalloproteinases
出版社: 食品暨應用生物科技學系所
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摘要: 薑活性成分之 6-gingerol 與 6-shogaol 屬植物之酚類化合物,其生理活性已被廣泛研究。文獻指出,薑活性成分對於抑制癌細胞增生、癌細胞侵入轉移與促使癌細胞凋亡等,具有化學預防 (chemoprevention) 之功效。雖然薑活性成分已知具有抗癌細胞轉移之活性,但對抑制人類肝癌細胞侵入轉移及抗血管新生作用仍未十分清楚,同時亦少有文獻比較兩者抗癌之效力。因此本研究探討薑活性成分之抗癌活性分成兩部分:(一) 薑活性成分對人類 Hep3B 肝癌細胞侵入轉移之抑制效應及釐清其分子機轉;(二) 評估薑活性成分抗血管新生之能力。 研究結果顯示,6-gingerol 及 6-shogaol 可藉由抑制訊息傳遞路徑 MAPKs 及 PI3K/AKT/mTOR 磷酸化,同時抑制 IκBα 磷酸化及降解作用,進而減少 NF-κB (nuclear factor-kappa B) 被活化成度,而無法被釋放進入細胞核內,以降低 NF-κB 之轉錄活性。因 NF-κB 活性受到抑制,減少了 uPA (urokinase plasminogen activator) 之基因及蛋白表現,並降低胞外 uPA 之活性,及其下游基質金屬蛋白酶 (matrix metalloproteinase) 2 與 9 之酵素活性,進而抑制人類 Hep3B 肝癌細胞侵入轉移能力。此外,薑活性成分亦可透過抑制核內轉錄因子 STAT3 (signal transducer and activator of transcription 3) 之活化,降低基質金屬蛋白酶 2 與 9 之基因轉錄活性,及增加 uPA 專一性抑制物 PAI (plasminogen activator inhibitor) -1 之基因及蛋白表現量,減少肝癌細胞之 uPA 及基質金屬蛋白酶之酵素活性。 利用人類肝癌細胞株 Hep3B 進行血管新生因子分泌之評估。薑活性成分 6-gingerol 可抑制 Hep3B 細胞分泌促血管新生因子 IL-8 (interleukin-8),而 6-shogaol 則可降低 Hep3B 細胞分泌促血管新生因子 VEGF (vascular endothelial growth factor)。當以抗血管新生模式評估時,薑活性成分可抑制人類臍帶靜脈內皮細胞 (human umbilical vein endothelial cells, HUVEC) 及大鼠動脈環 (rat aortic rings) 兩者之脈管生成 (tube formation)。而於雞胚胎絨毛尿囊膜 (chicken chorioallantoic membrance, CAM) 之體內模式中,以 6-gingerol 及 6-shogaol 培養可顯著抑制體內絨毛尿囊膜生成血管。 綜合上述,6-gingerol 及 6-shogaol 可藉由抑制訊息傳遞路徑 MAPKs 及 PI3K/AKT/mTOR,調降 NF-κB 及 STAT3 的活化,降低人類 Hep3B 肝癌細胞外 uPA、基質金屬蛋白酶 2 與 9 之酵素活性,而減緩肝癌細胞侵入轉移之能力。此外,6-gingerol 及 6-shogaol 分別可降低肝癌細胞分泌促血管新生因子 IL-8 與 VEGF。研究結果顯示,兩種薑活性分於體內及體外血管新生模式中,皆具有抗血管新生之能力。其中,具 α, β 不飽和羰基 (α, β-unsaturated carbonyl group) 之 6-shogaol,其抗轉移及抑制血管新生作用之能力,顯著優於 6-gingerol。
6-Gingerol and 6-shogaol are phenolic compounds in ginger, which possess chemopreventive properties such as anti-proliferation, anti-invasion, anti-metastasis and pro-apoptosis. However, the inhibitory effects of 6-gingerol and 6-shogaol on invasion, metastasis and angiogenesis of hepatocellular carcinoma remain unclear. In this study, we employed human hepatocarcinoma Hep3B cells as a model and investigated the inhibitory effects and molecular mechanisms of these two compounds on invasion and metastasis of the cells as well as angiogenesis in vivo and in vitro. The results showed that 6-gingerol and 6-shogaol suppressed the activation of NF-κB (nuclear factor-kappa B) via inhibiting the signaling of MAPKs and PI3K/AKT/mTOR and the phosphorylation and degradation of IκBα in Hep3B cells. By suppressing the activity of NF-κB, the mRNA and protein levels of uPA (urokinase plasminogen activator) and the activities of uPA and MMP (matrix metalloproteinase) -2/-9 were further decreased. Additionally, we found that the decrease of activity and transcriptional activities of uPA and MMP-2/-9 by 6-gingerol and 6-shogaol were also through inhibiting the activation of nuclear STAT3 (signal transducer and activator of transcription 3), and increasing the mRNA and protein levels of PAI-1. The results of the angiogenic evaluation indicated that the secretions of IL-8 (interleukin-8) and VEGF (vascular endothelial growth factor) in Hep3B cells were suppressed by the treatment with 6-gingerol and 6-shogaol, respectively. The tube formation of HUVEC (human umbilical vein endothelial cells) cells and rat aortic rings both were decreased by the treatment with 6-gingerol and 6-shogaol. 6-Gingerol and 6-shogaol also have the capability to inhibit the growth of blood vessels of CAM (chicken chorioallantoic membrance) in vivo. Taken together, 6-gingerol and 6-shogaol decrease the enzyme and transcriptional activities of uPA and MMP-2/-9 through inhibiting MAPKs and PI3K/AKT/mTOR signaling pathways and inactivating NF-κB and STAT3. Moreover, 6-gingerol and 6-shogaol inhibit the secretions of IL-8 and VEGF, respectively, and suppress the angiogenesis. Consequently, the invasion and metastasis of Hep3B cells were reduced. Chemically, it is presumed that the 6-shogaol exhibited a stronger effect on the suppressions of invasion and angiogenesis than 6-gingerol might be resulted from the α, β-unsaturated carbonyl group in the structure.
其他識別: U0005-1808201100132700
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