Roles of functional NFKB1 and βTrCP insertion/deletion polymorphisms in mRNA expression and epithelial ovarian cancer susceptibility

Abstract

ABSTRACT. Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological cancers. Nuclear factor-kappa B (NF-κB) is involved in carcinogenesis and in the development of EOC. The β-transducin repeat-containing protein (β-TrCP) is a positive regulator of the NF-κB signaling pathway. Recent studies have indicated that the -94 ins/del ATTG polymorphism in the promoter region of the NFKB1 gene, and the 9N ins/del polymorphism in the 3ꞌ-untranslated region of the β-TrCP gene are associated with increased susceptibility to a variety of cancers. We examined a potential association between these two polymorphisms and EOC. Genotypes were determined for 187 patients with EOC and 221 healthy control subjects, using the MassARRAY system. We found a significant association between the -94 ins/del ATTG genotype distribution and EOC. The frequency of the -94 del ATTG allele was significantly lower in EOC patients compared to healthy controls. The NF-κB mRNA level in cancer tissue was significantly correlated with -94 ins/del ATTG genotypes. Compared to the ATTG 1 /ATTG 1 phenotype, the NF-κB mRNA level was 2.089 and 1.257 times higher in the ATTG 2 (insertion)/ATTG 2 homozygote and the ATTG 1 (deletion)/ATTG 2 heterozygote, respectively. However, we found no evidence of association between the 9N ins/del polymorphism of the β-TrCP gene and EOC in this Chinese population. Based on these results, we suggest that the NF-κB -94 ins/del ATTG polymorphism is a risk factor for EOC susceptibility.

Effect of TP53 16-bp and β-TrCP 9-bp INS/DEL polymorphisms in relation to risk of breast cancer

“…With respect to the β-TrCP 9-bp polymorphism, we did not find any association between this INS/DEL polymorphism and risk of BC. In accordance with our data, this variation has not been associated with the risk of epithelial ovarian cancer (EOC) (Huo et al, 2013). In contrast, this polymorphism was shown to be correlated with the susceptibility to hepatocellular carcinoma in Chinese (Chen et al, 2010).…”

“…Association of 9-bp INS/DEL polymorphism in β-TrCP with β-TrCP mRNA expression has been reported. The presence of the 9-bp insertion allele in the 3′-UTR of β-TrCP has been shown to disrupt miR-920 binding, leading to relatively higher β-TrCP levels (Huo et al, 2013). Therefore, given the pivotal roles of p53, and β-TrCP proteins in the molecular pathology of tumorigenesis, the present study was aimed to evaluate the possible associations among three functional INS/DEL polymorphisms in the β-TrCP (9-bp) and TP53 (16-bp) genes and susceptibility to BC in an Iranian population.…”

Association of the genetic polymorphisms of NFKB1 with susceptibility to ovarian cancer

“…Our results provide direct evidence that a genetic change in NFKB1 is linked to ovarian cancer in humans, and extend the list of variants that may affect the development of ovarian cancer (Huo et al, 2013).…”

“…Individuals with the ATTG2 allele (insertion) had a 1.367-fold risk of ovarian cancer compared with non-carriers. Interestingly, the study by Huo et al (2013) demonstrated that the mRNA level of NFKB1 in EOC tissues significantly correlated with the -94 insertion/deletion ATTG genotype; the highest level of NFKB1 was observed in EOC ATTG2 homozygous tissues. This correlation may be associated with the enhanced expression and activity of p50.…”

“…An increasing number of studies have reported an association between rs28362491 and cancer risk, although conflicting results have been obtained (Lewander et al, 2007;Cai et al, 2013;Li et al, 2013). Moreover, only one study reported that rs28362491 in NFKB1 was significantly associated with ovarian cancer (Huo et al, 2013). In fact, a limited number of single nucleotide polymorphisms (SNPs) could not effectively capture the true causative SNPs in the NFKB1 gene owing to the weak linkage disequilibrium (LD) between them.…”