A novel circSLIT2-encoded SLIT2 isoform suppresses neural invasion in gastric cancer.

CircRNAs have emerged as critical regulators in various types of cancer. Neural invasion (NI) refers to a process whereby cancer cells infiltrate into the surrounding nerves and has been shown to predict poor prognosis in gastric cancer (GC). Accumulating evidence has suggested that tumor NI is a symbiotic relationship between cancer and nerves, which leads to the growth advantage for both. However, the involvement of circRNAs in the nerve-cancer cell crosstalk remains to be elucidated. In this study, downregulation of circSLIT2 expression was validated in GC tissues, especially in NI-positive GC tissues. Reduced circSLIT2 predicts poor prognosis in GC patients. CircSLIT2 inhibits the migration and neural invasion of GC cells both in vitro and in vivo. Mechanically, a novel peptide (SLIT2-284aa) translated by circSLIT2 was identified. SLIT2-284aa facilitates SLIT2/ROBO1 signaling via binding and inducing the ROBO1 membrane localization. Moreover, SLIT2-284aa enhances the association between ROBO1 and RhoGDI1, which suppresses RhoGDI1 phosphorylation and further reduces the release and activation of RhoA. Our work uncovers a novel circRNA-encoding peptide and a previously unknown SLIT2-284aa/ROBO1/RhoGDI1/RhoA signaling pathway that suppresses cell migration and neural invasion in GC, which provides a new prospect to understand the underlying biological mechanism of the nervous system in GC.