Abstract
The effect of immunotherapy for colorectal cancer (CRC) is limited due to anti-tumor immunosuppression. Circular RNAs (circRNAs) are also associated with tumor immunity. The aim of this study was to clarify the regulatory relationship between circRNA and anti-tumor immunosuppression in CRC. CircRNAs associated with CRC were identified using bioinformatic analysis and subsequently confirmed in clinical samples using qRT-PCR and in situ hybridization. The expression, clinical relevance, functional significance and clinical properties of circMVP in CRC specimens and cells were evaluated in vitro and in vivo. RNA pull-down, single-cell RNA sequencing, EMSA, RNA immunoprecipitation, chromatin immunoprecipitation, and polysome profiling assay were performed to confirm the underlying mechanism of circRNA. CircMVP (hsa_circ_0000688) expression was increased in CRC and correlated with poor prognosis in CRC patients. Increased circMVP expression activates proliferation, invasion, and tumorigenesis of CRC. In addition, we found that circMVP, by interacting with METTL3, stabilizes its expression in the nucleus and significantly enhances its mediated N6-methyladenosine (m6A) modification. Specifically, circMVP/METTL3 promoted the expression of β-catenin by directly acting on CTNNB1 mRNA. CircMVP/METTL3 further enhanced the expression of B7-H3 through the β-catenin signaling pathway. Notably, inhibition of circMVP expression significantly improved the efficacy of anti-B7-H3 immunotherapy in in vivo and in vitro models. CircMVP mediated CTNNB1 m6A modification by promoting METTL3 activation and inhibited B7-H3-dependent anti-tumor immune response in CRC. In conclusion, circMVP may be a predictor of CRC immune evasion and a potential therapeutic target.