Abstract
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.
Highlights
The vast majority of clinical and experimental evidences suggest that acute inflammation could promote tumor eradication by exerting an immunoprotective effect [1].tumor growth and invasion could be facilitated by chronic immune stimulation [1,2]
Since the onset of inflammation and carcinogenesis can be regulated by epigenetic events, we aimed to investigate the interplay among DNA methylation, miRNA expression, Int
Differential analysis of IL6, IL6R, and IL6ST revealed that these genes were significantly modulated in most of the selected the Cancer Genome Atlas (TCGA) tumor cohorts (n = 33) compared to normal tissues (Table 1)
Summary
Tumor growth and invasion could be facilitated by chronic immune stimulation [1,2] All these responses are orchestrated by soluble mediators (e.g., chemokines and cytokines) including tumor necrosis factor alpha (TNF-α) and Interleukin (IL-6) secreted by either host immune cells or tumor cells themselves [2,3,4]. Trans-signaling pathway through a soluble IL6-receptor-α (sIL-6R) which binds IL6 forming a complex able to interact and activate any cell expressing the receptor subunit glycoprotein gp130 [6,7]. The IL6 trans-signaling pathway is involved in most of the harmful effects of IL-6 in chronic inflammatory diseases and in cancer where it leads to switch on IL6-signaling in tumor or stromal cells expressing zero or low level of IL6R [7]
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