Circular MTHFD2L RNA-encoded CM-248aa inhibits gastric cancer progression by targeting the SET-PP2A interaction

The available targeted therapies for gastric cancer (GC) are still limited, so it is important to discover novel molecules as poten-tial treatment options. Proteins or peptides encoded by circular RNAs (circRNAs) are increasingly reported to play essential roles in malignancies. The aim of the present study was to iden-tify an undiscovered protein encoded by circRNA and explore its key role and molecular mechanism in GC progression. CircMTHFD2L (hsa_circ_0069982) was screened and validated as a downregulated circRNA with coding potential. The protein encoded by circMTHFD2L, named CM-248aa, was identified for the first time by immunoprecipitation and mass spectrom-etry. CM-248aa was significantly downregulated in GC, while its low expression was associated with advanced tumor-node -metastasis (TNM) stage and histopathological grade. Low expression of CM-248aa could be an independent risk factor for poor prognosis. Functionally, CM-248aa, instead of circMTHFD2L suppressed the proliferation and metastasis of GC in vitro and in vivo. Mechanistically, CM-248aa competi-tively targeted the acidic domain of SET nuclear oncogene (SET) and acted as an endogenous inhibitor of the SET-protein phosphatase 2A interaction to promote dephosphorylation of AKT, extracellular signal-regulated kinase, and P65. Our dis-covery revealed that CM-248aa could be a potential prognostic biomarker and endogenous therapeutic option for GC.

Automated summary

The aim of this study was to identify an undiscovered protein encoded by circRNA and explore its key role and molecular mechanism in gastric cancer progression. A downregulated circRNA with coding potential, circMTHFD2L, was found to encode a protein named CM-248aa. CM-248aa was significantly downregulated in gastric cancer and its low expression was associated with advanced tumor-node-metastasis stage and histopathological grade. Low expression of CM-248aa could be an independent risk factor for poor prognosis.