探討二氫楊梅素對於人類骨肉瘤細胞侵襲與轉移之影響及機制

二氫楊梅素 (Dihydromyricetin, DHM) 具有抗發炎、抗氧化、抗酒精中毒、降血壓、抗菌、以及抗腫瘤等多種生理功能。然而，二氫楊梅素對骨肉瘤和潛在機制的影響仍然不是很清楚。我們探討二氫楊梅素在人類骨肉瘤細胞株U2OS以及HOS細胞中的抗轉移特性。本研究發現，二氫楊梅素抑制人類骨肉瘤細胞株的遷移和侵襲，並透過下調尿激酶型血纖維蛋白溶解酶原活化因子 (Urokinase-type plasminogen activator, uPA) 的表現來抑制轉移。另外，由即時聚合酶連鎖反應和啟動子活性試驗的結果顯示，二氫楊梅素也降低uPA的mRNA表現與啟動子活性。此外，降低uPA啟動子與轉錄因子Specificity protein 1 (Sp-1) 和Nuclear factor-κB (NF-κB) 的結合，是導致抑制uPA表現量的原因。透過阻斷及誘導細胞外訊號調節激酶 (Extracellular signal-regulated kinase, ERK) 路徑，我們證實二氫楊梅素抑制uPA表現及細胞轉移是透過抑制ERK活化之訊息傳遞路徑。綜合以上研究結果，我們證實，二氫楊梅素是透過抑制ERK訊息傳遞路徑，進而抑制Sp-1和NF-κB進核的能力，來抑制其下游uPA基因的表現，最終抑制人類骨肉瘤細胞轉移的能力。二氫楊梅素可能是骨肉瘤抗轉移治療的潛力治療方式。

Dihydromyricetin (DHM) has diverse functions such as anti-inflammation, anti-oxidation, anti-alcohol intoxication, reducing blood pressure, anti-bacterial and anti-tumor properties. However, the effects of DHM on osteosarcoma and its underlying mechanisms are still not well understood. Herein, we investigated the anti-metastatic properties of DHM in human osteosarcoma U2OS and HOS cells. We found that DHM inhibits cell migration and invasion on osteosarcoma cell lines. In addition, DHM inhibits metastasis through down-regulating urokinase-type plasminogen activator (uPA) expression. Moreover, real-time polymerase chain reaction and promoter activity assays showed that DHM decreased uPA expression at the transcriptional level. Furthermore, inhibiton of uPA expression was associated with the suppression of promoter of Sp-1 and NF-κB on uPA. Regardless of blocking or activating of the extracellular signal-regulated kinase (ERK) pathway verified that DHM-suppressed uPA and cell invasion was through downregulating activation ERK pathway. In conclusion, our results suggest that DHM suppresses osteosarcoma invasion/migration via inhibiting ERK pathway mediated nuclear translocation of Sp-1 and NF-κB to further suppress uPA expression. DHM may be a potential therapeutic tool for metastasis of osteosarcoma.