DHA及EPA抑制巨噬細胞誘導胃癌細胞轉移能力之機轉研究

Abstract

攝取二十二碳六烯酸 (docosahexenoic acid, DHA)與二十碳五烯酸 (eicosapentaenoic acid, EPA) 已知與減低癌症發生率，降低癌症相關巨噬細胞 (tumor associated macrophage, TAM) 之數量有關，然而，目前尚未清楚了解其調控機制。 實驗結果發現，巨噬細胞可以增加胃癌細胞的轉移能力。利用聚合酶鏈鎖反應陣列發現巨噬細胞誘導胃癌細胞N87後質金屬蛋白酶(MMP1、MMP3與MMP10)基因表現量顯著上升。而DHA與EPA可抑制巨噬細胞所誘導的癌細胞轉移能力並降低其MMP10的表現，從核醣核酸(RNA)與蛋白質層面均獲得證實。我們也進一步利用zymography與抗體中和實驗得到驗證；另一方面，我們也證實DHA與EPA是藉由降低胃癌細胞的訊息傳遞分子ERK (extracellular signal regulated kinases)與STAT3 (signal transducers and activators of transcription 3) 表現量，進而降低MMP10的表現。 根據上述實驗結果，巨噬細胞會藉由磷酸化ERK與STAT3並增加MMP10的表現量，進而增加胃癌細胞的轉移能力；相反地，加入DHA 與EPA後會降低MMP10的表現。這些發現不但解釋了DHA與EPA的益處與效果，並且指出ERK / STAT3 / MMP10對於胃癌的治療，提供一個可能的治療標的。

Uptake of docosahexenoic acid (DHA)/eicosapentaenoic acid (EPA) improves the treatment of cancer and reduces tumor associated macrophage (TAM) count. However, the mechanism of this relationship is still unclear. In this study, macrophages enhanced gastric cancer cell migration ability and induced the differentially expressed matrix metalloproteinase genes (MMP1, MMP3, and MMP10) of N87 as identified by PCR array. Furthermore, DHA and EPA inhibited macrophage-enhanced cancer cell migration and attenuated MMP10 both at the RNA and protein level. The suppression of MMP10 expression was further verified by zymography and antibody blocking experiments. Additionally, DHA and EPA attenuated expression of macrophage-activated extracellular signal regulated kinases (ERK) and signal transducers and activators of transcription 3 (STAT3) in cancer cells. Attenuation was verified by demonstrating blockade with specific inhibitors, and thereby increased MMP10 expression. Accordingly, we hypothesized that macrophage enhances cancer cell migration through ERK and STAT3 phosphorylation and subsequent increased MMP10 expression and that DHA and EPA could attenuate these signals. These findings not only explain the beneficial effects of DHA/EPA, but also point to ERK/STAT3/MMP10 as the potential targets for gastric cancer treatment.