二十二碳六烯酸抑制 12-O-tetradecanoylphorbol-13-acetate 誘發MCF-7人類乳癌細胞fascin-1表現 是透過負向調控Wnt-1/β-catenin/STAT3α訊號路徑

乳癌為全球女性最常見的惡性腫瘤，癌細胞轉移是導致乳癌患者死亡的主要原因。研究證實，fascin-1蛋白除了可調節胚胎發育及維持細胞型態外，也在癌細胞移行和侵襲過程中扮演重要角色。本實驗室先前研究發現，乳癌細胞給予二十二碳六烯酸(docosahexaenoic acid, DHA) 處理，可抑制12-O-tetradecanoylphorbol-13-acetate (TPA)所誘發基質金屬蛋白酶(matrix metalloproteinase-9, MMP-9)及MCF-7乳癌細胞移行與侵襲。但是，DHA是否可以透過調節fascin-1表現而影響乳癌細胞轉移仍不清楚。本研究以MCF-7乳癌細胞為實驗模式，探討DHA對TPA誘發MCF-7乳癌細胞fascin-1基因表現及癌細胞轉移作用之影響。結果顯示，以100 ng/ml TPA處理細胞24小時後顯著增加Wnt-1、β-catenin、STAT3α、fascin-1總蛋白質表現量，預處理100 μM DHA則可降低TPA誘發的Wnt-1、β-catenin、STAT3α、fascin-1的表現。利用β-catenin siRNA刪除β-catenin基因表現後，可降低TPA誘發MCF-7乳癌細胞STAT3α、fascin-1的蛋白質表現及癌細胞移行。此外，DHA亦可抑制TPA短時間所誘發STAT3α磷酸化，一旦給予STAT3α抑制劑-WP1066可抑制TPA所誘發STAT3α與fascin-1 promoter 之DNA結合力。綜合上述結果，DHA抑制TPA誘發MCF-7乳癌細胞之移行，可能與負向調控Wnt-1/β-catenin/STAT3α訊號路徑，進而抑制fascin-1蛋白表現有關。

Breast cancer is the most commonly diagnosed cancer among woman all over the world. Altered function of components of the canonical Wnt/β-catenin signaling pathway is associated with cancer development, as multiple Wnt/β-catenin target gene such as fascin is regulator of cell proliferation and tumorigenesis. Previous study showed that fascin-1, an actin-bundling protein, plays an important role in cell migration and invasion. Docosahexaenoic acid (DHA; 22:6) has been shown to exhibit an anti-cancer effect in various human carcinoma cells, but the effect of DHA on fascin expression and metastasis of breast cancer cell is not fully clarified. In the present study, we studied the anti-metastatic potential of DHA in TPA-treated MCF-7 breast cancer cell. We found that TPA induced Wnt-1, β-catenin, STAT3α, fascin-1 protein expression as well as the phosphorylation of STAT3α in both dose- and time- dependent manner, and 100 μM DHA significantly inhibited TPA-induced Wnt-1, β-catenin, STAT3α, fascin-1 expression and the STAT3α phosphorylation. Furthermore, β-catenin siRNA knockdown TPA-induced STAT3α and fascin-1 protein expression in MCF-7 cells. These results indicate that attenuation of Wnt-1/β-catenin expression and their downstream signaling pathways are involved in DHA down-regulation of TPA-induced fascin-1 expression in MCF-7 human breast cancer cells.