TITLE

NFkB1 and NFkBIA Polymorphisms Are Associated with Increased Risk for Sporadic Colorectal Cancer in a Southern Chinese Population

AUTHOR(S)
Shunxin Song; Dianke Chen; Jiachun Lu; Jiawei Liao; Yanxin Luo; Zuli Yang; Xinhui Fu; Xinjuan Fan; Yisheng Wei; Lei Yang; Lei Wang; Jianping Wang
PUB. DATE
June 2011
SOURCE
PLoS ONE;2011, Vol. 6 Issue 6, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Nuclear factor kB (NFkB) plays a key role in the regulation of apoptosis. The function of NFkB is inhibited by binding to NFkB inhibitor (IkB), and disruption of the balance of NFkB and IkB is related to the development of many diseases, including tumors. Therefore, we hypothesized that the NFkB1 (-94del/insATTG) and NFkBIA (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 NFkBIA alter its gene expressions and functions and thus cancer risk. Results: We found that both NFkB1-94 ins/delATTG and NFkBIA 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(Ptrend<0.01). Moreover, luciferase assays showed that the G allele in the 39UTR significantly decreased NFkBIA mRNA stability and the A allele regulation by miRNA449a in vitro and that the NFkBIA protein expression levels of the AA+AG variant carriers were significantly higher in peritumoral tissues than those of the 2758GG genotype. Conclusion: NFkB1 and NFkBIA 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.
ACCESSION #
74275572

 

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