EIF4E-mediated biogenesis of circPHF14 promotes the growth and metastasis of pancreatic ductal adenocarcinoma via Wnt/β-catenin pathway

Abstract

BACKGROUND: CircRNAs are critically involved in the development and progression of various cancers. However, their functions and mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. METHODS: CircPHF14 (hsa_circ_0079440) was identified through the analysis of RNA sequencing data from PDAC and normal adjacent tissues. The biological functions of circPHF14 were then evaluated using CCK8, EdU, transwell, colony formation, wound healing assays, as well as pancreatic orthotopic xenograft and liver metastasis models. The interaction mechanisms between circPHF14 and PABPC1, which enhance the stability of WNT7A mRNA, were investigated through RNA pull-down, mass spectrometry, RNA Immunoprecipitation (RIP), and actinomycin D assays. The role of EIF4E in promoting circPHF14 biogenesis was examined using RIP, and western blotting. RESULTS: In this study, we observed a significant upregulation of circPHF14 in both clinical PDAC samples and cell lines. Functionally, circPHF14 enhanced PDAC proliferation and metastasis both in vitro and in vivo. Mechanistically, circPHF14 interacted with PABPC1 to stabilize WNT7A mRNA, thereby activating the Wnt/β-catenin pathway, which subsequently upregulated SNAI2 and initiated Epithelial-Mesenchymal Transition (EMT) in PDAC. Additionally, EIF4E was found to bind PHF14 pre-mRNA, facilitating circPHF14 biogenesis. Finally, we developed a lipid nanoparticle (LNP) formulation encapsulating sh-circPHF14 plasmids and confirmed its anti-tumor efficacy in a patient-derived xenograft (PDX) model. CONCLUSION: EIF4E-mediated biogenesis of circPHF14 stabilizes WNT7A mRNA via interaction with PABPC1, which subsequently activates the Wnt/β-catenin pathway, promoting the growth and metastasis of PDAC. These findings indicate that circPHF14 holds promise as a biomarker and therapeutic target for PDAC.