Melatonin inhibits lung metastasis of gastric cancer in vivo

Abstract

Aim: Melatonin shows therapeutic benefits in gastric cancer, but the mechanism underlying its anticancer effects remains elusive. The aim of this study was to determine whether melatonin inhibits lung metastasis in gastric cancer. Main methods: A lung metastasis model of gastric cancer was established in nude mice injected with human gastric adenocarcinoma MGC80-3 cells. Mice were divided into control, IL-1β-treated, melatonin-treated, and IL-1β plus melatonin-treated groups and analyzed for the formation of lung metastatic nodules by flow cytometry and hematoxylin and eosin staining. The mRNA expression of epithelial-mesenchymal transition (EMT) markers was assessed by RT-qPCR. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by gelatin zymography and their protein expression by western blotting and immunohistochemistry. The levels of NF-κB p65 and phosphorylated (p)-p65 were detected by immunohistochemistry. Key findings: The number of lung metastases in the IL-1β plus melatonin group was significantly lower and the sizes of nodules were smaller than those in the IL-1β group. Furthermore, melatonin reversed changes in the expression of EMT markers induced by IL-1β by increasing mRNA levels of β-catenin and E-cadherin and decreasing those of fibronectin, vimentin, and Snail compared to IL-1β. Treatment with IL-1β upregulated the expression and activities of MMP-2 and MMP-9 and expression of NF-κB p65 and phospho-p65 (p-p65), but melatonin alleviated these effects. Significance: Melatonin inhibited IL-1β-induced lung metastasis of gastric cancer through downregulation of MMP-2, MMP-9, and NF-κB p65 expression and activities. These findings provide a basis for potential use of melatonin as a supplementary therapy for patients with advanced gastric cancer.

Keywords

• Gastric cancer
• Metastasis
• IL-1β
• Melatonin
• Matrix metalloproteinase