Matrix metalloproteinase-1 expression is regulated by HIF-1-dependent and epigenetic mechanisms and serves a tumor-suppressive role in gastric cancer progression

The matrix metalloproteinase (MMP) family is associated with degradation of the extracellular matrix and is known to promote cancer invasion. The present study aimed to investigate the biological role of MMP-1 in gastric cancer cells and analyze the association between MMP-1 expression and the clinical outcomes of gastric cancer patients. In the present study, hypoxia accelerated invasion, accompanied by elevated MMP-1 expression in the gastric cancer cell line 58As9. Additionally, hypoxia-inducible factor-1 alpha (HIF-1 alpha) knock- down in 58As9 cells reduced MMP-1 expression under hypoxic conditions. Treatment with 5-aza-2-deoxycytidine and trichostatin A restored MMP-1 expression in the MMP-1-deficient cell lines MKN45 and MKN74. These results indicated that MMP-1 expression was controlled by both HIF-1 alpha-dependent and epigenetic mechanisms in gastric cancer cell lines. In addition, MMP-1 knockdown impaired the hypoxia-induced invasiveness of 58As9 cells, implicating MMP-1 in the elevated invasion. By contrast, knockdown enhanced the proliferative ability of 58As9 cells, whereby expression of cell cycle-related genes was subsequently altered. In nude mouse models, the knockdown accelerated the growth of xenograft tumor and the development of peritoneal dissemination. In an immunohistochemical study using 161 surgically resected cancer tissues, the Ki67 score was significantly higher in the group with low MMP-1 expression (P<0.001). Disease-free survival (DFS) and disease-specific survival (DSS) were both significantly reduced in patients with low MMP-1 expression (log-rank test; DFS: P=0.005; DSS: P=0.022). Multivariate analysis demonstrated that MMP-1 expression was an independent prognostic factor for DFS and DSS [DFS: HR=2.11 (1.22-3.92) P=0.005, DSS: HR=2.90 (1.23-8.50) P=0.012]. In conclusion, the present study indicated that MMP-1 may serve as a tumor-suppressive factor that inhibits gastric cancer progression, although it promoted invasion in vitro.