Crosstalk between IL-6/JAK/STAT3 and TNF-α/NF-κB signaling in colitis-associated colorectal cancer: epigenetic reprogramming, evidence boundaries, and opportunities for disease management
- 1Pu’er Traditional Chinese Medical Hospital
Abstract
Colitis-associated colorectal cancer (CAC) arises through the interaction of chronic mucosal inflammation, genetic evolution and durable changes in gene regulation. Among the inflammatory networks implicated in experimental and human studies, interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and tumor necrosis factor-alpha (TNF-α)/nuclear factor-kappaB (NF-κB) provide mechanistically informative routes by which cytokine exposure can influence DNA methylation, chromatin regulation and non-coding RNA programs. The best-supported examples include IL-6-associated DNMT1 activity and SOCS3 promoter hypermethylation, NF-κB p65/DNMT3A-associated miR-148a methylation, and STAT3-dependent miR-214 induction. These circuits should be regarded as representative mechanisms supported in specific model systems rather than universal initiating pathways in all human CAC lesions. Recent work further demonstrates that colonic stem cells can retain chromatin accessibility changes after experimental colitis resolves, providing direct evidence for durable inflammatory epigenetic memory. This review therefore separates evidence from human CAC or dysplasia, non-neoplastic inflammatory bowel disease (IBD) mucosa, inflammation-driven animal models, sporadic colorectal cancer (CRC) and cell-line systems. We integrate cytokine-linked epigenetic mechanisms with genetic and clonal evolution, define field cancerization operationally, and distinguish persistent epigenetic memory from transient inflammatory transcription. The translational sections are framed as an outlook: no epigenetic biomarker or epigenetic drug is currently established for CAC surveillance or prevention. We summarize the validation requirements for tissue, blood and stool biomarkers; classify therapeutic concepts by evidence level; and propose a patient-level roadmap for single-cell and spatial studies. The resulting framework emphasizes evidence-graded mechanisms and prospective validation rather than assuming that biologically plausible signals are clinically actionable.
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BibTeX
@article{yuan2026crosstalk,
title = {{Crosstalk between IL-6/JAK/STAT3 and TNF-α/NF-κB signaling in colitis-associated colorectal cancer: epigenetic reprogramming, evidence boundaries, and opportunities for disease management}},
author = {Jin Yuan and Jinping Liao and Fen Li and Denglu Xie and Zhiheng Zuo and Di Zhang and Tianwu Zhang},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1979583},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979583/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Crosstalk between IL-6/JAK/STAT3 and TNF-α/NF-κB signaling in colitis-associated colorectal cancer: epigenetic reprogramming, evidence boundaries, and opportunities for disease management
AU - Jin Yuan
AU - Jinping Liao
AU - Fen Li
AU - Denglu Xie
AU - Zhiheng Zuo
AU - Di Zhang
AU - Tianwu Zhang
PY - 2026
DA - 2026/10/26
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1979583
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979583/full
AB - Colitis-associated colorectal cancer (CAC) arises through the interaction of chronic mucosal inflammation, genetic evolution and durable changes in gene regulation. Among the inflammatory networks implicated in experimental and human studies, interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and tumor necrosis factor-alpha (TNF-α)/nuclear factor-kappaB (NF-κB) provide mechanistically informative routes by which cytokine exposure can influence DNA methylation, chromatin regulation and non-coding RNA programs. The best-supported examples include IL-6-associated DNMT1 activity and SOCS3 promoter hypermethylation, NF-κB p65/DNMT3A-associated miR-148a methylation, and STAT3-dependent miR-214 induction. These circuits should be regarded as representative mechanisms supported in specific model systems rather than universal initiating pathways in all human CAC lesions. Recent work further demonstrates that colonic stem cells can retain chromatin accessibility changes after experimental colitis resolves, providing direct evidence for durable inflammatory epigenetic memory. This review therefore separates evidence from human CAC or dysplasia, non-neoplastic inflammatory bowel disease (IBD) mucosa, inflammation-driven animal models, sporadic colorectal cancer (CRC) and cell-line systems. We integrate cytokine-linked epigenetic mechanisms with genetic and clonal evolution, define field cancerization operationally, and distinguish persistent epigenetic memory from transient inflammatory transcription. The translational sections are framed as an outlook: no epigenetic biomarker or epigenetic drug is currently established for CAC surveillance or prevention. We summarize the validation requirements for tissue, blood and stool biomarkers; classify therapeutic concepts by evidence level; and propose a patient-level roadmap for single-cell and spatial studies. The resulting framework emphasizes evidence-graded mechanisms and prospective validation rather than assuming that biologically plausible signals are clinically actionable.
SN - 1664-3224
ER -