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 analyses were used to compare expression patterns between mouse fibroblast L cells that stably express wild-type and a mutant form of Wnt5a to investigate Wnt5a-dependent gene expression. The expression of genes found to be regulated by Wnt5a 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 γ2, a subunit of the epithelial basement membrane protein laminin-5. Wnt5a induced the expression of laminin γ2 through the activation of protein kinase C and c-Jun-N-terminal kinase. The invasive activity of gastric cancer cells depended on laminin γ2; Wnt5a expression levels correlated with those of laminin γ2 in diffuse-scattered type gastric tumor samples from patients. Conclusions: Wnt5a contributes to gastric cancer progression by increasing metastatic potential. Wnt5a up-regulates laminin γ2 to mediate gastric cancer cell aggressiveness.
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