Gastrointestinal Institute of Sun Yat-Sen University, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.
PLoS One. 2011;6(6):e21726. doi: 10.1371/journal.pone.0021726. Epub 2011 Jun 30.
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.
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.
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.
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.
核因子 kappa B（NFκB）在调控细胞凋亡中发挥着关键作用。NFκB 的功能受到与 NFκB 抑制剂（IκB）结合的抑制，而 NFκB 和 IκB 之间平衡的破坏与许多疾病的发展有关，包括肿瘤。因此，我们假设 NFκB1（-94del/insATTG）和 NFκBIA（2758A>G）多态性与结直肠癌（CRC）易感性有关。
在一项基于医院的病例对照研究中，我们对 1001 例 CRC 患者和 1005 例年龄和性别匹配的无癌症对照进行了研究，使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对多态性进行了基因分型，并进行了荧光素酶检测和 Western 印迹分析，以确定 NFκBIA 中的遗传变异是否改变了其基因表达和功能，从而影响癌症风险。
我们发现，NFκB1-94ins/delATTG 和 NFκBIA 2758A>G 多态性均与 CRC 风险相关（OR=1.47；95%CI=1.14-1.86，和 OR=1.38；95%CI=1.14-1.66）。此外，当评估这两个多态性时，与 0 个变异等位基因（风险）相比，同时具有 2 个变异（风险）等位基因（2758GG 和-94ins/ins+del/ins）的联合基因型与 CRC 风险增加相关（OR=1.71；95%CI=1.23-2.38），并且在年龄<60 岁、女性、从不饮酒、从不吸烟、BMI 正常和有癌症家族史的亚组中，2 个变异（风险）等位基因的显著趋势更为明显（P（趋势）<0.01）。此外，荧光素酶检测表明，3'UTR 中的 G 等位基因显著降低了 NFκBIA mRNA 的稳定性，体外 miRNA449a 对 A 等位基因的调节作用，以及 AA+AG 变异携带者的 NFκBIA 蛋白表达水平在癌旁组织中明显高于 2758GG 基因型。
NFκB1 和 NFκBIA 多态性似乎共同导致 CRC 风险增加。这两个变体可能是中国南方人群 CRC 易感性的遗传修饰因子。
