探討Metformin合併使用Sorafenib抗肝細胞癌轉移之分子機制

肝癌患者往往會被診斷出癌細胞有轉移的症狀，而死於早期及遠端轉移發生。轉移是由一連串步驟所串連組成，包括細胞黏著、細胞外基質降解、細胞移行與侵襲。因此，能對抗轉移相關步驟的物質，就可能可以用來防止腫瘤細胞發生轉移，並增加癌症患者生存的機會。二甲雙胍(Metformin)是目前廣泛使用於治療第二型糖尿病的用藥。之前文獻顯示Metformin可以有效的抑制肝癌細胞的形成，但分子機制尚未清楚。本研究主要利用人類肝癌細胞株SK-Hep-1與HA22T/VGH為實驗材料，探討Metformin影響肝癌細胞侵襲與轉移的分子機制。本實驗中發現Metformin主要透過抑制ERK1/2、JNK1/2的磷酸化，進而抑制基質金屬蛋白-9 (matrix metalloproteinase-9 , MMP-9) 與尿激酶型血纖維蛋白溶解酶原活化因子(urokinase-type plasminogen activator, uPA)的表現與分泌，進一步發現Metformin會抑制轉錄因子NF-κB進入細胞核與MMP-9和uPA的啟動子(promoter)結合，進而抑制肝癌細胞的侵襲與轉移能力，另外將Metformin結合肝癌晚期標靶藥物Sorafenib，發現兩者藥物合併處理對於肝癌細胞的侵襲與轉移能力皆更顯著被抑制，綜合以上結果說明藥物合併治療具有協同作用，可以更有效的抑制肝癌細胞轉移與侵襲，為肝癌晚期病人的治療帶來一線曙光，冀望未來有機會發展為治療肝癌晚期的新策略。

Metformin has been shown to exert anti-cancer activities in several cancer cells and animal models. However, the molecular mechanisms of its anti-metastatic activities remain poorly understood and warrant further investigation. The aims of this study were to evaluate the ability of Metformin to inhibit the migration and invasion of hepatocellular carcinoma (HCC) and identify its effects on signaling pathways. Our data indicated that Metformin inhibits the migration and invasion of human HCC cells. Metformin was also found to significantly inhibit the expression and secretion of MMP-9 and uPA in HCC cells, and suppress the phosphorylation of ERK1/2 and JNK1/2. A treatment with an ERK1/2 inhibitor (PD98059) or JNK1/2 inhibitor (SP600125) enhanced the inhibitory effects of Metformin on the migration and invasion of HCC cells. Moreover, the Metformin-induced inhibition of MMP-9 and uPA promoter activity also blocked the nuclear translocation of NF-κB and its binding to the MMP-9 and uPA promoters, and these suppressive effects were further enhanced by PD98059 or SP600125. Moreover, Metformin markedly enhanced the anti-metastatic effects of Sorafenib. In conclusion, Metformin inhibited the migration and invasion of HCC cells by suppressing the ERK/JNK-mediated NF-kB-dependent pathway, and thereby reducing uPA and MMP-9 expressions. Additionally, a combination treatment with Metformin and Sorafenib yielded synergistic inhibitory effects in suppressing cell migration and invasion of HCC cells. These findings provide insight into the molecular mechanisms involved in the anti-metastatic effects of Metformin, as well as its ability to enhance the chemosensitivity of Sorafenib on HCC cells.