RBMS1-mediates the biogenesis of circNFIB promotes perineural invasion of pancreatic ductal adenocarcinoma via the L1CAM/MAPK pathway

Background: Circular RNAs (circRNAs) play a key regulatory role in various functional characteristics of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms underlying circRNA's involvement in the occurrence of perineural invasion (PNI) in PDAC remain unclear and require further investigation. Methods: Through circRNA sequencing, we identified the circNFIB (hsa_circ_0086376) that is highly associated with PNI in PDAC tissues. We then evaluated the promoting effect of circNFIB on PNI using various assays, including the Matrigel/dorsal root ganglia (DRG) model, DRG-matrix assay, transwell assay, orthotopic xenograft model, and in vivo model of neural infiltration. The interaction mechanism between circNFIB and IGF2BP3, which enhances L1CAM mRNA stability, was explored using RNA pulldown, mass spectrometry, RNA Immunoprecipitation (RIP), and actinomycin D assays. Additionally, the role of RBMS1 in promoting the biogenesis of circNFIB was investigated using RIP and Western blotting. Results: This study confirmed that circNFIB is significantly upregulated in PDAC samples and samples with high PNI. Both in vitro and in vivo experiments demonstrated its role in promoting PNI in PDAC. Mechanistically, circNFIB binds with IGF2BP3 in PDAC cells to enhance the stability of L1CAM mRNA, activating the ERK/MAPK signaling pathway, and facilitating PNI in PDAC. Additionally, we found that RBMS1 binds to the NFIB pre-mRNA and promotes the biogenesis of circNFIB. Finally, we verified circNFIB as a potential therapeutic target that can mitigate the anti-tumor effects of SCH772984 in vivo. Conclusion: RBMS1-mediated circNFIB interacts with IGF2BP3 to stabilize L1CAM mRNA, thereby activating the ERK/MAPK signaling pathway and promoting PNI in PDAC. This study provides a novel perspective on the molecular mechanisms underlying PNI in PDAC and lays the theoretical foundation for circNFIB as a potential therapeutic target for PDAC.