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

• Published in: Molecular therapy 2023-06, Vol.31 (6), p.1739-1755
• Main Authors: Liu, Haohan, Fang, Deliang, Zhang, Chaoyue, Zhao, Zirui, Liu, Yinan, Zhao, Shaoji, Zhang, Nu, Xu, Jianbo
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Proliferation - genetics; CircMTHFD2L; CM-248aa; gastric cancer; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs - genetics; Original; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; protein phosphatase 2A; RNA - genetics; RNA, Circular - genetics; SET nuclear oncogene; Stomach Neoplasms - pathology
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2023.04.013

The available targeted therapies for gastric cancer (GC) are still limited, so it is important to discover novel molecules as potential 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 identify 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 spectrometry. 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 competitively 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 discovery revealed that CM-248aa could be a potential prognostic biomarker and endogenous therapeutic option for GC. [Display omitted] Xu and colleagues report that circMTHFD2L and its encoded novel protein, CM-248aa, are both significantly downregulated in gastric cancer (GC). CM-248aa is identified as a novel tumor suppressor and an endogenous inhibitor of the SET-PP2A interaction, which negatively regulates the PI3K-AKT, MAPK, and NF-κB pathways to inhibit GC progression.