Genetic variation and alterations of genes involved in NFκB/TNFAIP3- and NLRP3-inflammasome signaling affect susceptibility and outcome of colorectal cancer

Abstract

Colorectal tumors are continuously exposed to an inflammatory environment, which together with mitogenic signals sustain several cancer hallmarks. Nuclear factor-kappa B (NFκB) is a major regulator of inflammation and variation in NFκB-associated genes could potentially be used as biomarkers to identify patients with increased risk of colorectal cancer (CRC) development, and/or a rapidly progressing disease. In this study, 348 CRC cases and 806 randomly selected healthy individuals from southeastern Sweden were examined with regard to seven polymorphisms in NFκB pathway-associated genes. Log-rank-tests and Cox proportional hazard regression analysis examined the association between the polymorphisms and CRC-specific survival, whereas chi-square tests and logistic regression analysis were used to test for associations between the polymorphisms and CRC susceptibility. Gene expression and loss of heterozygosity analyses of TNFAIP3 were carried out in a subset of tumors to assess its role as a tumor suppressor in CRC. Heterozygous and polymorphic TNFAIP3 (rs6920220), heterozygous NLRP3 (Q705K) and polymorphic NFκB -94 ATTG ins/del genotypes were found to be associated with poorer survival in patients diagnosed with invasive CRC (aHR = 5.2, 95% CI: 2.5-10.9, P < 0.001). TNFAIP3 mRNA levels were significantly decreased in tumors compared with adjacent non-neoplastic mucosa (P < 0.0001) and loss of heterozygosity of 6q23.3 (TNFAIP3) was detected in 17% of cases, whereas only 2.5% of the investigated specimens displayed TNFAIP3 gene mutations. We propose that TNFAIP3 (rs6920220), NLRP3 (Q705K) and NFκB -94 ATTG ins/del polymorphisms are associated with poor survival in patients with advanced CRC and may be used as prognostic markers. Experimental results indicate that TNFAIP3 may act as a tumor suppressor in CRC.

Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers

“…103 Mechanistically, TNFAIP3 inhibits nuclear factor-κB signaling by controlling the ubiquitination of proteins related to nuclear factor-κB that is involved in tumorigenesis. It has been established that the composition of gut microbes may associate with the risk for CRC, and thus whether TNFAIP3 is involved in host responses to gut microbiota deserves further investigation.…”

Expression of inflammasome-related genes in bladder cancer and their association with cytokeratin 20 messenger RNA

“…Several studies demonstrate the role of NLR inflammasomes in cancer. For example, NLRP3 gene polymorphisms have been associated with melanoma [16], myeloma [17], and colorectal cancer [18]. In the present study we characterized NLR genes in urine sediments and evaluated their contribution to predict bladder cancer together with CK20.…”

Inhibitory effect of snake venom toxin on NF-κB activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression

“…(Naugler and Karin 2008;Sarkar and Li 2008;Ungerback et al 2012). Many studies found that NF-κB is overexpressed in a variety of cancer, including cervical cancer (Barkett and Gilmore 1999;Gilmore et al 2002;Luque and Gelinas 1997;Rayet and Gelinas 1999).…”