Abstract
Our recent study demonstrated that higher expression of N-myc downregulated gene 1 (NDRG1) is closely correlated with poor prognosis in gastric cancer patients. In this study, we asked whether NDRG1 has pivotal roles in malignant progression including metastasis of gastric cancer cells. By gene expression microarray analysis expression of NDRG1 showed the higher increase among a total of 3691 up-regulated genes in a highly metastatic gastric cancer cell line (58As1) than their parental low metastatic counterpart (HSC-58). The highly metastatic cell lines showed decreased expression of E-cadherin, together with enhanced expression of vimentin and Snail. This decreased expression of E-cadherin was restored by Snail knockdown in highly metastatic cell lines. We next established stable NDRG1 knockdown cell lines (As1/Sic50 and As1/Sic54) from the highly metastatic cell line, and both of these cell lines showed enhanced expression of E-cadherin and decreased expression of vimentin and Snail. And also, E-cadherin promoter-driven luciferase activity was found to be increased by NDRG1 knockdown in the highly metastatic cell line. NDRG1 knockdown in gastric cancer cell showed suppressed invasion of cancer cells into surround tissues, suppressed metastasis to the peritoneum and decreased ascites accumulation in mice with significantly improved survival rates. This is the first study to demonstrate that NDRG1 plays its pivotal role in the malignant progression of gastric cancer through epithelial mesenchymal transition.
Highlights
Gastric cancer is one of the most common malignancies in Japan and other Asian countries
We focused on one gene named N-myc downstream regulated gene 1 (NDRG1) because it was found to be markedly upregulated in the highly metastatic gastric cancer cell lines compared to their counterpart cells
We have previously reported that N-myc downregulated gene 1 (NDRG1) is closely correlated with tumor angiogenesis and poor survival in patients with gastric cancer, suggesting that NDRG1 is a predictive biomarker for malignant progression of gastric cancer [9]
Summary
Gastric cancer is one of the most common malignancies in Japan and other Asian countries. Yanagihara et al [5] first established the HSC-58 cell line from human scirrhous gastric cancer, and established two sublines, 58As1 and 58As9, with a high potential for peritoneal dissemination and lymph node metastasis by repeated orthotopic inoculation of HSC-58 cells into the gastric wall of athymic mice [6,7] These sublines often cause accumulation of ascites after orthotopic implantation and show increased expression of genes encoding proteases and proteins involved in cell adhesion, cell motility, proliferation and angiogenesis [6]. They grow selectively in the gastric submucosa, and invade the deeper layer to reach the serosal plane of the stomach [7]. It remains unclear why they have acquired such a high potential for metastasis during selection
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