Laminin γ2 Mediates Wnt5a-Induced Invasion of Gastric Cancer Cells

BACKGROUND & AIMS: Wnt5a expression stimulates in vitro migration and invasion of cultured gastric cancer cells by an unknown mechanism and is also correlated with aggressiveness of gastric tumors. The aim of this study was to show that Wnt5a is involved in metastasis of gastric cancer cells in vivo and to explore the molecular mechanism by which Wnt5a regulates migration and invasion. METHODS: In an experimental liver metastasis assay, Wnt5a-knockdown gastric cancer cells were injected into the spleens of nude mice. Microarray anatyses were used to compare expression patterns between mouse fibroblast L cells that stably express wild-type and a inurant form of Wnt5a to investigate Wnt5a-dependent gene expression. The expression of genes found to be regulated by Writ5a was investigated in cultured gastric cancer cells. Immunohistochemical analyses were performed to measure levels of Wnt-regulated gene products in 153 gastric cancer samples. RESULTS: Knockdown of Wnt5a in gastric cancer cells reduced the number of liver metastases that formed in nude mice. Microarray analyses indicated that Wnt5a activity induced expression of the gene encoding laminin gamma 2, a subunit of the epithelial basement membrane protein laminin-5. Wnt5a induced the expression of laminin gamma 2 through the activation of protein kinase C and c-Jun-N-terminal kinase. The invasive activity of gastric cancer cells depended on laminin gamma 2; Wnt5a expression levels correlated with those of laminin gamma 2 in diffuse-scattered type gastric tumor samples from patients. CONCLUSIONS: Wnt5a contributes to gastric cancer progression by increasing metastatic potential. Wnt5a up-regulates laminin gamma 2 to mediate gastric cancer cell aggressiveness.