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.

Protein phosphatase 2A-B55δ enhances chemotherapy sensitivity of human hepatocellular carcinoma under the regulation of microRNA-133b

“…Furthermore, PP2A activation shows a promising anti-tumor effect in breast cancer [ 25 ]. Our previous studies have shown that the genetic variant -241 (-/G) (rs11453459) in the 5’-flanking region of PPP2R1A contributes to the decreased risk of HCC in a southern Chinese Han population [ 26 ]. Moreover, other studies have demonstrated that the regulation of regulatory B subunits of PP2A (PP2A-Bs), such as B55β and B56γ, play important roles in cancer development or treatment [ 27 ].…”

Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics

“…Interestingly, the observed frequency of CAPs in our phosphatase interaction network is much higher than expected from a random network of similar size (p < 2.2 À16 ) ( Figure 7A, inset) and reveals many links to various forms of cancer. For example, the PP2A network harbors five CAPs including the PP2A regulatory subunit alpha (2AAA/PPP2R1A), which is also a CAP related to several carcinomas such as ovarian and hepatocellular carcinomas ( Figure 7A) (Chen et al, 2013;Rahman et al, 2013). The other four CAPs are lipoma-preferred partner (LPP), FGFR1 oncogene partner (FR1OP), CCDC6, and ZCHC8 ( Figure 7A).…”

IL-6-6331 (T/C, rs10499563) is Associated with Decreased Risk of Gastric Cancer in Northern Chinese

“…Similar studies have reported that the relation between gene polymorphism and cancer risk was more obvious in certain subgroup, which may result from different characteristic of the host (e.g. environmental factors and immune conditions) (Yang et al, 2011;He et al, 2012;Chen et al, 2013).…”