Abstract
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.
Highlights
Reversible phosphorylation of proteins is an important regulatory mechanism for maintaining cell homeostasis that regulates cell growth, proliferation, apoptosis, survival and differentiation [1]
The genotype frequencies of above single nucleotide polymorphisms (SNPs) among controls were all in agreement with the Hardy-Weinberg equilibrium (P.0.05 for all)
The associations of the two promising SNPs were further confirmed in the validation set as shown in Table 2, the rs11453459G genotypes were significantly associated with an increased risk of lung cancer (OR = 1.28, 95%CI = 1.00–1.63, P = 0.048), and the rs1255722AA genotype conferred an increased lung cancer risk compared to other genotypes (OR = 1.32, 95%CI = 0.98–1.77) with a borderline statistically significance (P = 0.069)
Summary
Reversible phosphorylation of proteins is an important regulatory mechanism for maintaining cell homeostasis that regulates cell growth, proliferation, apoptosis, survival and differentiation [1]. It balances phosphorylation-dependent signal transduction pathways by virtue of the phosphorylation with protein kinases and dephosphorylation with protein phosphatases. Multiple evidences have indicated that the aberrant activity of phosphorylation involves the development of several cancers (e.g., lung cancer), which was caused by activated oncogenic kinases and inactivated phosphatases [2]. Dysfunctional PP2A has been observed in various human cancers including lung cancer, which may be due to genetic or epigenetic changes in different PP2A subunit genes [17,18]
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