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The mechanism and function of cancer metastasis-associated microRNAs (miRNAs) have not been completely examined. Using a miRNA array, we previously determined that a significantly decreased level of miR-516a-3p was closely associated with the peritoneal dissemination of scirrhous gastric cancers. We previously established HSC-58 cells from a scirrhous gastric cancer patient, and we further isolated metastatic cells (58As9) from ascites in nude mice upon repeated orthotopic transplantation of HSC-58. In our previous report (Takei Y, et al. Cancer Res, 2011), we showed that the miR-516a-3p expression was significantly low and the peritoneal dissemination was significantly high in 58As9 compared with HSC-58. To augment the decreased expression of miR-516a-3p in 58As9 cells, we successfully prepared a cell line (58As9-miR-516a-3p) that stably overexpressed the miRNA. In the present study, we showed that orthotopic transplantation of 58As9-miR-516a-3p into nude mice resulted in significantly decreased primary tumor growth, ascites, and peritoneal dissemination. Moreover, the transplanted nude mice showed long survival time, probably due to the small amount of ascitic fluids pooled. The miRNA directly targeted sulfatase 1, which works to remove a sulfate group from heparan sulfate proteoglycans on the cell surface, and promotes the release of membrane-bound Wnt ligands into medium. Significantly increased concentrations of Wnt3a, Wnt5a, and nuclear-accumulated b-catenin were observed in 58As9 cells, and in 58As9-miR-516a-3p, all of the levels were attenuated. Anti-metastatic therapy via injection of the miR-516a-3p expression vector/atelocollagen mixture into 58As9 orthotopic tumors in nude mice resulted in significantly prolonged survival along with the inhibition of ascites and peritoneal dissemination. Our findings thus indicate that the miR-516a-3p-sulfatase 1-Wnt b-catenin route can be targeted to block the peritoneal dissemination of scirrhous gastric cancers.

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The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine