PVT1-104aa derived from the 8q24 gene desert promotes colorectal cancer tumorigenesis.

BACKGROUND: Current therapeutic outcomes for advanced colorectal cancer (CRC) remain suboptimal, and chemotherapy-based regimens continue to be the mainstay of treatment. Circular RNAs (circRNAs) can serve as templates for translating short peptides or proteins, and the resulting products actively regulate malignant tumour progression, making them attractive therapeutic targets. METHODS: We identified the novel protein PVT1-104aa translated from circPVT1, which is generated by back-splicing of the non-coding PVT1 gene. Its expression and clinical significance were examined in CRC clinical specimens and cell lines. Proliferation, metastasis, and tumour growth were assessed by CCK-8, colony formation, transwell, wound healing, and xenograft syngeneic tumour models. Mechanistic studies were performed by immunoprecipitation, ubiquitination assays, and protein half-life analysis. The relationship between PVT1-104aa, c-Myc, and PD-L1 was evaluated by promoter reporter assays, ChIP-qPCR, and immunohistochemistry. The therapeutic efficacy of combining PVT1-104aa inhibition with anti-PD-L1 therapy was tested in vivo. RESULTS: PVT1-104aa was significantly overexpressed in CRC and correlated with poor patient prognosis. Functionally, it drove tumour progression by promoting proliferation and metastasis. Mechanistically, PVT1-104aa enhanced c-Myc phosphorylation at Ser62, disrupted the c-Myc-FBW7 interaction, and thereby inhibited ubiquitin-mediated degradation of c-Myc, as shown by accelerated c-Myc turnover upon PVT1-104aa knockdown. In addition, PVT1-104aa regulated PD-L1 expression through c-Myc. Combining anti-PVT1-104aa with anti-PD-L1 therapy suppressed CRC growth and increased CD4(+) and CD8(+) T cell infiltration in xenograft syngeneic tumour models and CRC tissues. CONCLUSIONS: Our results uncover a pathogenic role of the PVT1-originated molecular species PVT1-104aa and suggest that targeting this pathway represents a promising therapeutic strategy for CRC treatment. KEY POINTS: Circ-PVT1 is upregulated in CRC patients and encoded a novel protein: PVT1-104aa. PVT1-104aa promotes CRC progression and predicts worse prognosis. PVT1-104aa enhance Myc expression through inhibition of Myc ubiquitination. PVT1-104aa regulate PD-L1 expression of CRC cells and modulate T cells infiltration in vivo.