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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Targeted therapies for gastric cancer (GC) remain limited, necessitating the discovery of novel therapeutic molecules.
• Circular RNAs (circRNAs) and their encoded proteins are emerging as significant players in cancer development and progression.

Purpose of the Study:

• To identify a novel protein encoded by a circRNA and elucidate its role and mechanism in GC progression.
• To investigate circMTHFD2L and its encoded protein as potential diagnostic and therapeutic targets for GC.

Main Methods:

• Screening and validation of circRNAs with coding potential in GC.
• Identification of the circRNA-encoded protein (CM-248aa) using immunoprecipitation and mass spectrometry.
• In vitro and in vivo functional assays to assess CM-248aa's impact on GC proliferation and metastasis.
• Mechanistic studies involving protein-protein interactions and signaling pathway analysis (SET, PP2A, AKT, ERK, P65).

Main Results:

• CircMTHFD2L was identified as a downregulated circRNA with coding potential in GC.
• The novel protein CM-248aa, encoded by circMTHFD2L, was identified and found to be significantly downregulated in GC.
• Low CM-248aa expression correlated with advanced TNM stage and poor histopathological grade, serving as an independent risk factor for poor prognosis.
• CM-248aa suppressed GC cell proliferation and metastasis in vitro and in vivo.
• CM-248aa functions by inhibiting the SET-protein phosphatase 2A interaction, leading to dephosphorylation of AKT, ERK, and P65.

Conclusions:

• CM-248aa is a novel circRNA-derived protein with tumor-suppressive functions in gastric cancer.
• Downregulation of CM-248aa is associated with poor prognosis in GC patients.
• CM-248aa represents a promising prognostic biomarker and a potential therapeutic target for gastric cancer.