Exosomal circSPIRE1 mediates glycosylation of E-cadherin to suppress metastasis of renal cell carcinoma

Metastasis is the main cause of mortality in renal cell carcinoma (RCC). Circular RNAs (circRNAs) involvement in RCC metastasis has been described, although the underlying mechanisms remain unknown. We evaluated recurring lung-metastasis cases using patient-derived xenograft models and isolated a highly metastatic clone. CircSPIRE1 was identified as a metastasis-inhibiting circRNA in clinical cohort and xenograft models. Mechanistically, circSPIRE1 suppressed mesenchymal state through regulating ELAV like RNA binding protein 1-mRNA binding, and upregulating polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and KH domain RNA binding protein (QKI) expression. GALNT3 promoted glycosylation and cytomembrane localization of E-cadherin. QKI formed a positive feedback loop to enhance circSPIRE1 expression. Meanwhile, exosomal circSPIRE1 suppressed angiogenesis and vessel permeability. Our work reveals a non-canonical route for circRNAs in RCC to suppress metastasis. Furthermore, a nanomedicine consisting of circSPIRE1 plasmid suppressed metastasis formation. In conclusion, circSPIRE1 may be a predictor of metastasis and a potential therapeutic target of metastatic RCC.