Work

Pain - related methylation driver genes affect the prognosis of pancreatic cancer patients by altering immune function and perineural infiltration

Year: 2025

Type: article

Abstract: Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Source: Frontiers in Genetics

DOI: 10.3389/fgene.2025.1600883

Authors: Chencheng Zhang, Weiwei Xu, Xudong Chen, Xingdan Wang, Xiaopeng Cui, Wenjing Zhao

Institutions: Nantong University, Nantong Tumor Hospital, Affiliated Hospital of Nantong University

Language: English

Topic: Pancreatic and Hepatic Oncology Research

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801