Roles of membrane-Anchoring ARHGAP fusions in peritoneal metastasis of gastric and pancreatic cancer.. Homo sapiens

Diffuse-type gastric cancer (DGC) frequently metastasizes to the peritoneal cavity and causes malignant ascites. Although recent studies revealed that RHOA mutation and CLDN18-ARHGAP6/26 fusions are a hallmark of DGC, their roles are largely unknown. Here, we report the roles of two novel ARHGAP fusions (RP2-ARHGAP6 and OCLN-ARHGAP26) and the above CLDN18-ARHGAP26 fusion in ascites-derived DGC cell lines. A series of experiments revealed that X-ARHGAP6 /26 fusion acts as an inhibitor of RhoA and further suggested that the ARHGAP6 fusion induces cell-adhesion loss and maintains a putative ALDH-high cancer stem cell population, whereas the ARHGAP26 fusion evades apoptosis. Notably, these ARHGAP6/26 fusions were frequently found not only in the ascites of DGC but also in that of pancreatic cancer (12% and 38%, respectively). Together, these data demonstrate that ARHGAP6/26 fusions are useful for developing therapeutics and diagnostics for peritoneal metastasis control of DGC and pancreatic cancer. We used microarrays to identify gene sets regulated by RP2-ARHGAP6-centered signaling in DGC cells. Overall design: We established two ARHGAP6 shRNA-expressing clones from RP2-ARHGAP6 harbored DGC cell line (NSC-10X1aF). In addition to these clones, control shRNA-expressing NSC-10X1aF cells were also established as control. Total 6 samples (2 independent biological experiments for each cell line) were analyzed by microarray.