title: Role of a novel functional variant in the PPP2R1A promoter on the regulation of PP2A-Aalpha and the risk of hepatocellular carcinoma.
abstract: Previously, we identified the genetic variant -241 (-/G) (rs11453459) in the PP2A-Aα gene (PPP2R1A) promoter and demonstrated that this variant influences the DNA-binding affinity of nuclear factor-kappa B (NF-κB). In this study, we further confirmed that the transcriptional activity of PPP2R1A may be regulated by NF-κB through the functional genetic variant -241 (-/G). Moreover, we also demonstrated that the methylation status of CpG islands in the promoter of PPP2R1A influences the activity of this gene promoter. Few studies have examined the role of this -241 (-/G) variant in genetic or epigenetic regulation in hepatocellular carcinoma (HCC). To investigate whether this functional variant in the PPP2R1A promoter is associated with the risk of HCC and confirm the function of the -241 (-/G) variant in the HCC population, we conducted a case-control study involving 251 HCC cases and 252 cancer-free controls from a Han population in southern China. Compared with the -241 (--) homozygote, the heterozygous -241 (-G) genotype (adjusted OR  = 0.32, 95% confidence interval (CI)  = 0.17-0.58, P<0.001) and the -241 (-G)/(GG) genotypes (adjusted OR  = 0.38, 95% CI  = 0.22-0.67, P  = 0.001) were both significantly associated with a reduced risk of HCC. Stratification analysis indicated that the protective role of -241 (-G) was more pronounced in individuals who were ≤ 40 years of age, female and HBV-negative. Our data suggest that the transcriptional activity of PPP2R1A is regulated by NF-κB through the -241 (-/G) variant and by the methylation of the promoter region. Moreover, the functional -241 (-/G) variant in the PPP2R1A promoter contributes to the decreased risk of HCC. These findings contribute novel information regarding the gene transcription of PPP2R1A regulated by the polymorphism and methylation in the promoter region through genetic and epigenetic mechanisms in hepatocarcinogenesis.
authors.affiliation: Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Hui-Feng
authors.initials: HF
authors.lastname: Chen
authors.forename: Jian-Rong
authors.initials: JR
authors.lastname: Mai
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Wan
authors.forename: Yan-fang
authors.initials: YF
authors.lastname: Gao
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Lin
authors.forename: Song-Zi
authors.initials: SZ
authors.lastname: Wang
authors.forename: Yu-Xi
authors.initials: YX
authors.lastname: Chen
authors.forename: Chen-Zi
authors.initials: CZ
authors.lastname: Zhang
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Xia
authors.forename: Kun
authors.initials: K
authors.lastname: Liao
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Lin
authors.forename: Zhong-Ning
authors.initials: ZN
authors.lastname: Lin
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D054648:Protein Phosphatase 2 / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B; C517191:PPP2R1A protein, human; D054648:Protein Phosphatase 2
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