Work

METTL3/IGF2BP3 mediates ORC6 via N6-methyladenosine modification to promote the progression of pancreatic ductal adenocarcinoma

Year: 2025

Type: article

Abstract: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is recognized globally as one of the most lethal tumours, and effective biomarkers to diagnose PDAC early are needed. ORC6, a subunit of the origin recognition complex (ORC), initiates DNA replication and ensures genomic stability. Previous studies have indicated that ORC6 is procarcinogenic in various cancers, yet its role in PDAC remains uninvestigated. METHODS: We evaluated the relationships between ORC6 expression and the clinical features of patients with PDAC with the TCGA, GTEx, and GEO databases. The role of ORC6 in PDAC cells was explored by RNA interference in vitro and in vivo. Next, we verified the effect of the METTL3/IGF2BP3/ORC6 axis on PDAC progression by western blotting, RT-qPCR, RNA immunoprecipitation, and methylated RNA immunoprecipitation. Finally, transcriptome analysis was performed to explore the influence of ORC6 on p53 in PDAC cells. RESULTS: Elevated ORC6 levels were observed in PDAC cells, which correlated with poorer clinical outcomes. Both in vivo and in vitro experiments demonstrated that ORC6 knockdown suppressed proliferation and promoted apoptosis. Additionally, we demonstrated that METTL3/IGF2BP3 interacted with ORC6 mRNA via N6-methyladenosine modification to improve ORC6 mRNA stability. Transcriptomic analysis and experiments indicated that ORC6 promoted PDAC progression by inhibiting serine-15 phosphorylation in p53. CONCLUSION: Our findings validate the role of ORC6 in PDAC and support the hypothesis that the METTL3/IGF2BP3/ORC6/p53 axis may be a novel therapeutic target for PDAC, and inhibiting this axis may be an advantageous therapeutic strategy for curing PDAC.

Source: Gene

DOI: 10.1016/j.gene.2025.149468