Hsa_circ_0058495-mediated IGF2BP2 ubiquitination and m6A modification of MEKK1 promote the progression of PDAC.

Background

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with dismal clinical outcomes. We identified hsa_circ_0058495 as significantly upregulated in PDAC tissues and PDAC cell-derived exosomes, where it contributes to tumor proliferation and invasion. The molecular mechanisms underlying its oncogenic function, however, remain incompletely understood.

Methods

Differential circRNA expression was profiled by RNA sequencing. The functional role of hsa_circ_0058495 and its molecular interactions were interrogated through Western blotting, RT-qPCR, co-immunoprecipitation, RNA pull-down, and RNA immunoprecipitation assays. Confocal microscopy and PET/CT imaging were employed to delineate its biological effects in vitro and in vivo.

Results

Hsa_circ_0058495 was enriched in PDAC-derived exosomes and stabilized IGF2BP2 by preventing TRIM25-mediated ubiquitination and attenuating autophagy-dependent degradation. Stabilized IGF2BP2 enhanced the stability of MEKK1 mRNA, leading to sustained ERK1/2 phosphorylation and consequent promotion of PDAC cell proliferation and invasion. Moreover, exosomal hsa_circ_0058495 facilitated M2 macrophage polarization, thereby fostering an immunosuppressive tumor microenvironment.

Conclusions

Hsa_circ_0058495 promotes PDAC progression by stabilizing IGF2BP2 and activating the MEKK1-ERK signaling cascade, while exosomal transfer of hsa_circ_0058495 drives M2 macrophage polarization to reinforce tumor-associated immunosuppression. These findings establish hsa_circ_0058495 as a pivotal regulator of PDAC progression and underscore its potential utility as both a diagnostic biomarker and a therapeutic target.