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Reduced promoter methyilation of MyD88 and ASC/TMS1 genes in tumor tissue of patients with lung carcinoma

Aberrant DNA methylation of promoter region CpG islands is associated with gene silencing and serves as an alternative to mutation-induced inactivation of tumor suppressor genes in human cancers. Chronic inflammation and infection have been recognized among major risk factors for the most common types of cancer. Several lines of evidences are linking cancer, inflammation and infection. Transcription factor nuclear factor-κB (NF-κB), major inducer of inflammation is activated by many cancer risk factors (cigarettes smoke) and is constitutively active in most cancer. Activation and controlling mechanisms of inflammation and infection are regulated by NF-κB and almost exclusively relied on receptors of innate immunity, known as Pattern Recognition Receptors (PRR). Thus, suppression of these proinflammatory pathways may provide opportunities for both prevention and treatment of cancer.The aim of presented study was to evaluate methylation status of ASC/TMS1 (Apoptosis-associated speck-like protein containing a CARD/Target of methylation- induced silencing-1) and MyD88 genes (Myeloid differentiation primary response 88), key adaptor molecules in innate immunity signaling. Here we found that both MyD88 and ASC/TMS1 exhibit reduced methylation status of promoter regions in tumor tissues from patients diagnosed with lung cancer, comparing to healthy tissue. These results were also confirmed on protein level. Reduced methylation status in tumor tissue, of both MyD88 and ASC/TMS1, correlate with higher protein expression and vice versa. To confirm our findings on mRNA level we performed pathway- focused gene expression analysis of 84 genes involved in TLR and NOD signaling pathway using RT-qPCR approach (RT 2 Profiler TM PCR Array Human Inflammasomes). We found that expression of MyD88 mRNA in tumor tissue is unchanged compared to healthy lung tissue, while level ASC mRNA, gene involved in inflammasome formation, is up- regulated in tumor compared to healthy lung tissue. Also, we detected tumor specific cytokine profile on mRNA level ; up-regulation of cytokines as IL-18 and IL-1B and down-regulation of cytokines as IL-12A, IL33 and IL-6.

methylation, promoter, inflammation, cancer, MyD88, ASC/TMS1

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