ORIGINAL RESEARCH article
Front. Genet.
Sec. Cancer Genetics and Oncogenomics
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1600883
This article is part of the Research TopicClinical prediction models in cancer through bioinformaticsView all 16 articles
Pain -related methylation driver genes affect the prognosis of pancreatic cancer patients by altering immune function and perineural infiltration
Provisionally accepted
- 1Cancer Research Center Nantong, Nantong Tumor Hospital, Nantong, Jiangsu Province, China
- 2Department of Oncology,Nantong Tumor Hospital, Nantong, Jiangsu Province, China
- 3Department of Pathology, Nantong Tumor Hospital, Nanjing, Jiangsu Province, China
- 4Department of Radiotherapy, Nantong Tumor Hospital, Nantong, Jiangsu Province, China
- 5Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
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The malignant progression of pancreatic cancer (PC) is frequently accompanied by intractable pain mediated through perineural invasion (PNI), yet the underlying epigenetic regulatory mechanisms remain elusive.This study aims to elucidate the role of DNA methylation in the pathogenesis of PC pain, including its interactive effects with the nervous and immune systems.Integrating multi-omics data from TCGA-PAAD (Pancreatic adenocarcinoma), we identified methylation driver genes (MDGs) using the MethylMix algorithm. By intersecting MDGs with pain-related gene sets and conducting multi-step regression modeling, we established a five-gene prognostic signature (PSMB8/COL17A1/BICC1/CTRC/TRIP13). Next, in order to elucidate the underlying mechanisms, we conducted differential expression analysis, protein-protein interaction network analysis, functional enrichment analysis, and single-cell sequencing. Additionally, we quantified immune infiltration using CIBERSORT and TIMER.Pain-related MDGs are enriched in immune regulation, extracellular matrix reorganization, and cation channel activity, constituting the "immune-neural axis" of epigenetic regulation. The prognostic five-gene signature significantly stratifies patient survival risk (HR=3.83, p=1.4e-8), with its methylation levels positively correlated with CD4+ T cell infiltration and negatively correlated with dendritic cells. Model-derived differentially expressed genes exhibited dual immune-neural tropism at single-cell resolution, prominently enriched in presynaptic signaling and synaptic vesicle cycling. Mechanistically, MDGs orchestrate pain progression through PNI-associated neural remodeling and K+ channel-mediated neuronal hypersensitization.This study establishes a visceral pain model centered on pancreatic parenchymal nociception rather than secondary neural effects, and for the first time proposes an interconnected regulatory network linking epigenetic modifications, immune reprogramming, and neural plasticity, revealing dual pain pathogenesis mechanisms: 1) immune microenvironment reshaping that potentiates neuroinflammation, and 2) direct ion channel regulation enhancing neuronal excitability. These findings provide a mechanistic foundation for developing methylation-based prognostic biomarkers and multimodal analgesic therapeutic strategies targeting the immuno-neural nexus.
Keywords: Pancreatic carcinoma, DNA Methylation, perineural invasion (PNI), neuropathic pain, immune microenvironment, Prognostic signature
Received: 03 Apr 2025; Accepted: 15 Aug 2025.
Copyright: © 2025 Zhang, Xu, Chen, Wang, Cui and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Wenjing Zhao, Cancer Research Center Nantong, Nantong Tumor Hospital, Nantong, 226361, Jiangsu Province, China
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