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

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.112753
Zhuo Wu, Zhou Fang, Liangtang Zeng, Dingwen Zhang, Yu Zhou, Rufu Chen
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引用次数: 0

Abstract

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.

rbms1介导circNFIB的生物发生,通过L1CAM/MAPK通路促进胰腺导管腺癌的神经周围侵袭。
背景:环状rna (circRNAs)在胰腺导管腺癌(pancreatic ductal adencarcinoma, PDAC)的各种功能特征中发挥着关键的调节作用。然而,circRNA参与PDAC中围神经侵袭(PNI)发生的机制尚不清楚,需要进一步研究。方法:通过circRNA测序,我们在PDAC组织中鉴定出与PNI高度相关的circNFIB (hsa_circ_0086376)。然后,我们通过各种实验评估了circNFIB对PNI的促进作用,包括基质/背根神经节(DRG)模型、DRG基质实验、transwell实验、原位异种移植模型和体内神经浸润模型。通过RNA下拉、质谱、RNA免疫沉淀(RIP)和放线菌素D检测,探讨了circNFIB和IGF2BP3之间增强L1CAM mRNA稳定性的相互作用机制。此外,利用RIP和Western blotting研究RBMS1在促进circNFIB生物发生中的作用。结果:本研究证实circNFIB在PDAC样本和高PNI样本中显著上调。体外和体内实验均证实了其在PDAC中促进PNI的作用。在机制上,circNFIB与PDAC细胞中的IGF2BP3结合,增强L1CAM mRNA的稳定性,激活ERK/MAPK信号通路,促进PDAC中的PNI。此外,我们发现RBMS1结合NFIB前mrna并促进circNFIB的生物发生。最后,我们在体内验证了circNFIB是一个潜在的治疗靶点,可以减轻SCH772984的抗肿瘤作用。结论:rbms1介导的circNFIB与IGF2BP3相互作用稳定L1CAM mRNA,从而激活ERK/MAPK信号通路,促进PDAC的PNI。本研究为PNI在PDAC中的分子机制提供了新的视角,并为circNFIB作为PDAC的潜在治疗靶点奠定了理论基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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