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Functional genetic polymorphisms in PP2A subunit genes confer increased risks of lung cancer in southern and eastern Chinese.

ABSTRACT:

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Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and functions as a tumor suppressor that negatively regulates the activity of some oncogenic kinases. Recent studies have reported that PP2A expression was suppressed during lung carcinogenesis, we there hypothesized that the single nucleotide polymorphisms (SNPs) in PP2A subunit genes may affect PP2A function and thus contribute to lung cancer susceptibility. In a two-stage case-control study with a total of 1559 lung cancer patients and 1679 controls, we genotyped eight putative functional SNPs and one identified functional SNP (i.e., rs11453459) in seven major PP2A subunits (i.e., PPP2R1A, PPP2R1B, PPP2CA, PPP2R2A, PPP2R2B, PPP2R5C, PPP2R5E) in southern and eastern Chinese. We found that rs11453459G (-G/GG) variant genotypes of PPP2R1A and the rs1255722AA variant genotype of PPP2R5E conferred increased risks of lung cancer (rs11453459, -G/GG vs. -: OR = 1.31, 95% CI = 1.13-1.51; rs1255722, AA vs.

Ag/gg

OR?=?1.27, 95% CI = 1.07-1.51). After combined the two variants, the number of the adverse genotypes was positively associated with lung cancer risk in a dose-response manner (P trend = 5.63 × 10(-6)). Further functional assay showed that lung cancer tissues carrying rs1255722AA variant genotype had a significantly lower mRNA level of PPP2R5E compared with tissues carrying GG/GA genotypes. However, such effect was not observed for the other SNPs and other combinations. Our findings suggested that the two functional variants in PPP2R1A and PPP2R5E and their combination are associated with lung cancer risk in Chinese, which may be valuable biomarkers to predict risk of lung cancer.

SUBMITTER: Yang R

PROVIDER: S-EPMC3812212 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Functional genetic polymorphisms in PP2A subunit genes confer increased risks of lung cancer in southern and eastern Chinese.

Yang Rongrong R Yang Lei L Qiu Fuman F Zhang Lisha L Wang Hui H Yang Xiaorong X Deng Jieqiong J Fang Wenxiang W Zhou Yifeng Y Lu Jiachun J

PloS one 20131029 10

PMID: 24204789

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Project description:BackgroundProtein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese.MethodsIn a case-control study with a total of 541 PLC patients and 547 controls in Guangxi province of Southern China, we genotyped six putatively functional polymorphisms (rs10421191G>A, rs11453459del>insG, rs1560092T>G, rs7840855C>T, rs1255722G>A and rs10151527A>C) of three PP2A subunit genes (PPP2R1A, PPP2R2A and PPP2R5E) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform.ResultsThe rs11453459insG variant genotypes (ins/ins+del/ins) of PPP2R1A were found to be significantly associated with an increased risk of PLC compared with the del/del genotype (adjusted OR = 1.290, 95% CI = 1.009-1.650), and the number of insert G allele worked in a dose-dependent manner (P trend= 0.007). The stratified analysis showed that the effects of rs11453459insG variant genotypes were more evident in the subgroup who drink pond-ditch water (adjusted OR = 3.051, 95% CI = 1.264-7.364) than those never drink (P = 0.041). The carriers of rs11453459 del/ins genotype had a significantly lower level of PPP2R1A mRNA expression in liver cancer tissues than those of the del/del genotype (P = 0.021). Furthermore, we used microcystin-LR, a carcinogen presents in the pond-ditch water, to treat human peripheral blood mononuclear cells and found that the cells from carriers of rs11453459insG variant genotypes induced more DNA oxidative damages than those from the del/del genotype carriers (P < 0.001).ConclusionThese findings suggest that the PPP2R1A rs11453459del>insG polymorphism is associated with an increased risk of PLC, especially for persons with a history of drinking pond-ditch water. This insertion/deletion polymorphism may be a susceptible biomarker for PLC in Chinese.

Project description:Nuclear factor ?B (NF?B) plays a key role in the regulation of apoptosis. The function of NF?B is inhibited by binding to NF?B inhibitor (I?B), and disruption of the balance of NF?B and I?B is related to the development of many diseases, including tumors. Therefore, we hypothesized that the NF?B1 (-94del/insATTG) and NF?BIA (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 NF?BIA alter its gene expressions and functions and thus cancer risk.We found that both NF?B1-94 ins/delATTG and NF?BIA 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 NF?BIA mRNA stability and the A allele regulation by miRNA449a in vitro and that the NF?BIA protein expression levels of the AA+AG variant carriers were significantly higher in peritumoral tissues than those of the 2758GG genotype.NF?B1 and NF?BIA 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.

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Functional genetic polymorphisms in PP2A subunit genes confer increased risks of lung cancer in southern and eastern Chinese.

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Functional genetic polymorphisms in PP2A subunit genes confer increased risks of lung cancer in southern and eastern Chinese.

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