Novel Insights into Epigenetic Regulation of IL6 Pathway: In Silico Perspective on Inflammation and Cancer Relationship

IL-6 pathway is abnormally hyperactivated in several cancers triggering tumor cell growth and immune system inhibition. Along with genomic mutation, the IL6 pathway gene expression can be affected by DNA methylation, microRNAs, and post-translational modifications. Computational analysis was perform...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-09, Vol.22 (18), p.10172
Main Authors: Candido, Saverio, Tomasello, Barbara Maria Rita, Lavoro, Alessandro, Falzone, Luca, Gattuso, Giuseppe, Libra, Massimo
Format: Article
Language:English
Subjects:
Cancer
Computer applications
Correlation analysis
Cytokines
Deoxyribonucleic acid
DNA
DNA methylation
Down-regulation
Epigenetics
Gene expression
Glycoproteins
Growth factors
Immune system
Inflammation
Inflammatory diseases
Interleukin 6
Interleukin 6 receptors
Leukemia
Lymphoma
Medical prognosis
MicroRNAs
miRNA
Mutation
Pathogenesis
Patients
Post-translation
Sarcoma
Survival
Survival analysis
Testicular cancer
Transcription factors
Tumor necrosis factor-TNF
Tumorigenesis
Tumors
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Summary:IL-6 pathway is abnormally hyperactivated in several cancers triggering tumor cell growth and immune system inhibition. Along with genomic mutation, the IL6 pathway gene expression can be affected by DNA methylation, microRNAs, and post-translational modifications. Computational analysis was performed on the Cancer Genome Atlas (TCGA) datasets to explore the role of IL6, IL6R, IL6ST, and IL6R transmembrane isoform expression and their epigenetic regulation in different cancer types. IL6 was significantly modulated in 70% of tumor types, revealing either up- or down-regulation in an approximately equal number of tumors. Furthermore, IL6R and IL6ST were downregulated in more than 10 tumors. Interestingly, the correlation analysis demonstrated that only the IL6R expression was negatively affected by the DNA methylation within the promoter region in most tumors. Meanwhile, only the IL6ST expression was extensively modulated by miRNAs including miR-182-5p, which also directly targeted all three genes. In addition, IL6 upregulated miR-181a-3p, mirR-214-3p, miR-18a-5p, and miR-938, which in turn inhibited the expression of IL6 receptors. Finally, the patients’ survival rate was significantly affected by analyzed targets in some tumors. Our results suggest the relevance of epigenetic regulation of IL6 signaling and pave the way for further studies to validate these findings and to assess the prognostic and therapeutic predictive value of these epigenetic markers on the clinical outcome and survival of cancer patients.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms221810172