NFκB1 and NFκBIA Polymorphisms Are Associated with Increased Risk for Sporadic Colorectal Cancer in a Southern Chinese Population

BACKGROUND: Nuclear factor κB (NFκB) plays a key role in the regulation of apoptosis. The function of NFκB is inhibited by binding to NFκB inhibitor (IκB), and disruption of the balance of NFκB and IκB is related to the development of many diseases, including tumors. Therefore, we hypothesized that the NFκB1 (-94del/insATTG) and NFκBIA (2758 A>G) polymorphisms were associated with colorectal cancer (CRC) susceptibility. METHODS: In a hospital-based case–control study of 1001 CRC patients and 1005 cancer-free controls frequency matched by age and sex, we genotyped polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and performed luciferase assays and Western blotting analysis to identify whether genetic variants in NFκBIA alter its gene expressions and functions and thus cancer risk. RESULTS: We found that both NFκB1-94 ins/delATTG and NFκBIA 2758 A>G polymorphisms were correlated with CRC risk (OR = 1.47; 95%CI = 1.14–1.86, and OR = 1.38; 95% CI = 1.14–1.66, respectively). Furthermore, when evaluated these two polymorphisms together, the combined genotypes with 2 variant (risk) alleles (2758GG and -94ins/ins+del/ins) were associated with an increased risk of CRC (OR = 1.71; 95% CI = 1.23–2.38) compared to 0 variant, and the significant trend for 2 variant (risk) alleles were more pronounced among subgroups of aged <60 years, women, never drinkers, never smokers, persons with a normal BMI and those with a family history of cancer(P(trend)<0.01). Moreover, luciferase assays showed that the G allele in the 3′UTR significantly decreased NFκBIA mRNA stability and the A allele regulation by miRNA449a in vitro and that the NFκBIA protein expression levels of the AA+AG variant carriers were significantly higher in peritumoral tissues than those of the 2758GG genotype. CONCLUSION: NFκB1 and NFκBIA polymorphisms appear to jointly contribute to risk of CRC. These two variants may be a genetic modifier for CRC susceptibility in this southern Chinese population.