engleski

Association of EMAST and NLRP3 inflammasome activating pathway in development of sporadic colorectal cancer

Colorectal cancer (CRC) represents significant health problem worldwide, with majority of cases appearing in sporadic form as a result of complex genetic and environmental interactions. Accumulation of genetic alterations most frequently develops through defective mismatch repair, known as microsatellite instability pathway. Increasing evidence indicates a complex link between inflammation and microsatellite alterations at tetranucleotide repeats (EMAST), associating them with modified CRC progression towards metastasis and poor survival in patients. Colonic inflammation, that can be result of immune response to dysbiosis and damage, leads to activation of key inflammatory pathway mediated by NLRP3 inflammasome. Dysregulated activation of this pathway can occur on different levels and it is involved in tumor pathogenesis. However, the role of NLRP3 inflammasome pathway in sporadic colorectal cancer development and progression remains unclear. The purpose of our study was to investigate an association between several polymorphisms in genes associated with NLRP3 inflammasome activating pathway and microsatellite instability type EMAST in patients with sporadic CRC. A group of 160 EMAST-characterized sporadic colorectal tumors is examined with regard to polymorphisms in genes for TLR4, NLRP3 and CARD8, as well as caspase-1 and cytokines IL-6, IL-1β and IL-18. Microsatellite instability type EMAST was performed by VNTR analysis using 5 tetranucleotide markers. Real-time PCR–SNP analysis of polymorphisms was performed according to the manufacturer's instructions. In examined population, patients were stratified according to their specific genotypes. Analysis revealed significant difference in genotype distribution between patients with EMAST-stable tumors and patients with tumors showing EMAST-type of microsatellite instability. We observed statistically significant association between tumors with positive/high microsatellite instability type EMAST and polymorphisms in the NLRP3 (Q705K) (p=0, 02) and TLR4 (Thr399Ile) (p=0, 01) genes. Our results suggest that dysregulated activity of TLR4 receptor and certain parts of NLRP3 activating pathway might have a role in EMAST- related development of sporadic CRC.

sporadic colorectal cancer ; EMAST ; NLRP3 inflammasome

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