Eicosapentaenoic Acid and Docosahexaenoic Acid Inhibit Macrophage-induced Gastric Cancer Cell Migration by Attenuating the Expression of Matrix Metalloproteinase 10

Uptake of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) improves the treatment of cancer and reduces tumor-associated macrophage 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 polymerase chain reaction array. Furthermore, DHA and EPA inhibited macrophage-enhanced cancer cell migration and attenuated MMP10 at both 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 kinase (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.