GPX1

Gene Summary

Gene:GPX1; glutathione peroxidase 1
Aliases: GPXD, GSHPX1
Location:3p21.3
Summary:This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans. This protein is one of only a few proteins known in higher vertebrates to contain selenocysteine, which occurs at the active site of glutathione peroxidase and is coded by UGA, that normally functions as a translation termination codon. In addition, this protein is characterized in a polyalanine sequence polymorphism in the N-terminal region, which includes three alleles with five, six or seven alanine (ALA) repeats in this sequence. The allele with five ALA repeats is significantly associated with breast cancer risk. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:glutathione peroxidase 1
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (48)
Pathways:What pathways are this gene/protein implicaed in?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Genetic Predisposition
  • Case-Control Studies
  • Trinucleotide Repeats
  • Bladder Cancer
  • Genotype
  • Mutation
  • TGFB1
  • Selenium
  • Tumor Markers
  • rac GTP-Binding Proteins
  • Sunburn
  • Lung Cancer
  • Selenium-Binding Proteins
  • beta Carotene
  • Thioredoxin Reductase 2
  • Glutathione Peroxidase
  • Sequence Deletion
  • Catalase
  • Gene Expression
  • Antioxidants
  • Breast Cancer
  • Selenocysteine
  • Alleles
  • Oxidative Stress
  • Cancer Gene Expression Regulation
  • Single Nucleotide Polymorphism
  • Stomach Cancer
  • Risk Factors
  • Messenger RNA
  • Selenoproteins
  • Chromosome 3
  • RHOA
  • Genetic Variation
  • Odds Ratio
  • Promoter Regions
  • Liver Cancer
  • Polymorphism
  • Superoxide Dismutase
  • Prostate Cancer
  • Publication Bias
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Research Design
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: GPX1 (cancer-related)

Jin L, Li D, Alesi GN, et al.
Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth.
Cancer Cell. 2015; 27(2):257-70 [PubMed] Article available free on PMC after 09/02/2016 Related Publications
How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.

Nalkiran I, Turan S, Arikan S, et al.
Determination of gene expression and serum levels of MnSOD and GPX1 in colorectal cancer.
Anticancer Res. 2015; 35(1):255-9 [PubMed] Related Publications
BACKGROUND/AIM: Oxidative stress plays a role on the development of colorectal cancer. Manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPX1) are crucial in regulating oxidative balance and its stabilization. Possible mechanisms of action of these enzymes in various types of cancers require further investigation. We aimed to determine expression levels of these genes and their effects on protein levels in serum of patients with colorectal cancer.
MATERIALS AND METHODS: Expression levels of genes were determined using Real Time-Polymerase chain reaction in 35 patients with colorectal cancer. We used enzyme-linked immunosorbent assay to determine MnSOD and GPX1 levels.
RESULTS: We found significant differences in GPX1 expression between tumor and normal tissues, with a 2-fold decrease in tumor tissues (p<0.05). However, although no significant difference was found between the expression of MnSOD gene in tumor and that in normal tissues, there was a 1.13-fold change in expression. We observed no relationship between expressions of either gene and their levels in serum.
CONCLUSION: The GPX1 gene may play a critical role in the development of colorectal cancer.

Bănescu C, Trifa AP, Voidăzan S, et al.
CAT, GPX1, MnSOD, GSTM1, GSTT1, and GSTP1 genetic polymorphisms in chronic myeloid leukemia: a case-control study.
Oxid Med Cell Longev. 2014; 2014:875861 [PubMed] Article available free on PMC after 09/02/2016 Related Publications
Oxidative damage at the DNA level may be promoted by high levels of reactive oxygen species (ROS), leading to genomic instability and increased neoplastic risk. Superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) enzymes are implicated in the prevention of DNA damage by ROS. The aim of the study was to investigate the relationships between CAT C262T, GPX1 Pro198Leu, MnSOD Ala16Val, GSTM1, GSTT1, and GSTP1 Ile105Val polymorphisms and the risk of CML. No association was observed between CML and variant genotypes of GPX1, MnSOD, GSTM1, and GSTT1 polymorphisms in any of the investigated cases. Our study suggests that the homozygous variant genotype of the GSTP1 Ile105Val gene polymorphisms may be associated with the risk of developing CML (OR = 2.5; 95% CI = 1.08-5.7; P value = 0.02), while the heterozygous genotype of the CAT C262T polymorphism seems to have a protective effect against CML (OR = 0.59, 95% CI = 0.39-0.89, P value = 0.01). In most cases, no association was found between laboratory parameters and prognostic factors and the variant genotype of investigated gene polymorphisms. We concluded that CAT, GPX, MnSOD, GSTM1, and GSTT1 gene polymorphisms are not associated with the risk of CML. Variant genotype of the GSTP1 Ile105Val gene polymorphisms may contribute to the risk of developing CML.

Gerstenberger JP, Bauer SR, Van Blarigan EL, et al.
Selenoprotein and antioxidant genes and the risk of high-grade prostate cancer and prostate cancer recurrence.
Prostate. 2015; 75(1):60-9 [PubMed] Article available free on PMC after 01/01/2016 Related Publications
BACKGROUND: Observational studies suggest an inverse association between selenium and risk of prostate cancer. However, randomized controlled trials of selenium supplementation have reported conflicting results. Thus, we examined plasma selenium and selenium-related genes in relation to risk of high-grade prostate cancer and prostate cancer recurrence among men initially diagnosed with non-metastatic disease.
METHODS: We measured plasma selenium and genotyped 73 single nucleotide polymorphisms in TXNRD1, TXNRD2, GPX1, GPX3, GPX4, SEP15, SEPP1, SELENBP1, OGG1, and CAT among 568 men with non-metastatic prostate cancer who underwent radical prostatectomy. We examined associations between plasma selenium, genotypes, and risk of high-grade prostate cancer (Gleason grade ≥8 or 7 with primary score ≥4; n = 111) using logistic regression, and risk of prostate cancer recurrence (61 events; 3.8 y median follow-up) using Cox proportional hazards regression.
RESULTS: Plasma selenium was not associated with risk of high-grade prostate cancer or prostate cancer recurrence. Less common alleles of rs11913319 in TXNRD2 and rs125701 in OGG1 were associated with an increased risk of high-grade prostate cancer. We observed associations between the risk of prostate cancer recurrence and multiple SNPs in TXNRD1, TXNRD2, GPX3, and SEP15. These associations were no longer statistically significant after adjustment for multiple comparisons.
CONCLUSIONS: Among men with non-metastatic prostate cancer, there is suggestive evidence that genetic variation in selenoproteins and related antioxidant enzymes may be associated with risk of high-grade disease at diagnosis and prostate cancer recurrence.

Bera S, Weinberg F, Ekoue DN, et al.
Natural allelic variations in glutathione peroxidase-1 affect its subcellular localization and function.
Cancer Res. 2014; 74(18):5118-26 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
Glutathione peroxidase 1 (GPx-1) has been implicated in the etiology of several common diseases due to the association between specific allelic variations and cancer risk. The most common among these variations are the codon 198 polymorphism that results in either a leucine or proline and the number of alanine repeat codons in the coding sequence. The molecular and biologic consequences of these variations remain to be characterized. Toward achieving this goal, we have examined the cellular location of GPx-1 encoded by allelic variants by ectopically expressing these genes in MCF-7 human breast carcinoma cells that produce undetectable levels of GPx-1, thus achieving exclusive expression in the same cellular environment. A differential distribution between the cytoplasm and mitochondria was observed, with the allele expressing the leucine-198 polymorphism and 7 alanine repeats being more cytoplasmically located than the other alleles examined. To assess whether the distribution of GPx-1 between the cytoplasm and mitochondria had a biologic consequence, we engineered derivative GPx-1 proteins that were targeted to the mitochondria by the addition of a mitochondria targeting sequence and expressed these proteins in MCF-7 cells. These cells were examined for their response to oxidative stress, energy metabolism, and impact on cancer-associated signaling molecules. The results obtained indicated that both primary GPx-1 sequence and cellular location have a profound impact on cellular biology and offer feasible hypotheses about how expression of distinct GPx-1 alleles can affect cancer risk. Cancer Res; 74(18); 5118-26. ©2014 AACR.

Barr PM, Miller TP, Friedberg JW, et al.
Phase 2 study of imexon, a prooxidant molecule, in relapsed and refractory B-cell non-Hodgkin lymphoma.
Blood. 2014; 124(8):1259-65 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
Lymphoma cells are subject to higher levels of oxidative stress compared with their normal counterparts and may be vulnerable to manipulations of the cellular redox balance. We therefore designed a phase 2 study of imexon (Amplimexon/NSC-714597), a prooxidant molecule, in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Imexon was administered at 1000 mg/m(2) IV daily for 5 days in 21-day cycles. Gene expression analysis performed on pretreatment tumor specimens included 13 transcripts used to generate a redox signature score, previously demonstrated to correlate with lymphoma prognosis. Twenty-two patients were enrolled having follicular (n = 9), diffuse large B-cell (DLBCL) (n = 5), mantle cell (n = 3), transformed follicular (n = 2), small lymphocytic (n = 2), and Burkitt (n = 1) lymphoma. The most common grade 3/4 adverse events were anemia (14%) and neutropenia (9%). The overall response rate was 30%, including responses in follicular lymphoma (4 of 9) and DLBCL (2 of 5). Gene expression analyses revealed CD68 and the redox-related genes, GPX1 and SOD2, as well as a higher redox score to correlate with clinical responses. Therefore, pretreatment markers of oxidative stress may identify patients likely to respond to this therapeutic approach. This trial was registered at www.clinicaltrials.gov as #NCT01314014.

Oskina NA, Еrmolenko NA, Boyarskih UA, et al.
Associations between SNPs within antioxidant genes and the risk of prostate cancer in the Siberian region of Russia.
Pathol Oncol Res. 2014; 20(3):635-40 [PubMed] Related Publications
In the present study we investigated the association of a number of polymorphic changes in antioxidant system genes (SNPs rs1050450 in the GPX1 gene, rs1695 and rs1138272 in the GSTP1 gene and rs4880 in the MnSOD gene) with the risk of prostate cancer. The association of disease stage and PSA levels with specific genotypes was also analyzed. A study was conducted with the participation of 736 Russian men. We compared the frequency of occurrence of the studied alleles in patients with prostate cancer (392) to a control group (344) of men without a history of cancer. Genotyping was performed by real-time PCR. Comparison of frequencies of alleles and genotypes were performed using logistic regression analysis. No statistically significant association with the risk of prostate cancer was found for any of the SNPs studied (p > 0.05). For SNP rs1695 in the GSTP1 gene, a correlation with cancer disease stage was observed: a GG genotype is significantly more common in patients with PCa in the 3rd and 4th stage than 1st and 2nd (OR[95%CI] = 2.66[1.15-6.18], p = 0.02). Both studied SNPs of GSTP1 gene are associated with the level of PSA: the GG rs1695 and the TT rs1138272 genotypes are associated with higher PSA levels (p = 1.5*10(-3)).

Geybels MS, van den Brandt PA, Schouten LJ, et al.
Selenoprotein gene variants, toenail selenium levels, and risk for advanced prostate cancer.
J Natl Cancer Inst. 2014; 106(3):dju003 [PubMed] Related Publications
Lower selenium levels have been associated with increased risk of prostate cancer (PCa), and genetic variation in the selenoprotein genes selenoprotein P (SEPP1) and glutathione peroxidase 1 (GPX1) is thought to modify this relationship. We investigated whether the association between toenail selenium levels and advanced PCa risk in the prospective Netherlands Cohort Study is modified by common genetic variation in SEPP1 and GPX1. Toenail clippings were used to determine selenium levels and to isolate DNA for genotyping. This case-cohort study, which included 817 case subjects with advanced PCa and 1048 subcohort members, was analyzed with Cox regression models. All statistical tests were two-sided. Three genetic variants were associated with advanced (stage III/IV or IV) PCa risk: SEPP1 rs7579 (lower risk; P trend = .01), GPX1 rs17650792 (higher risk; P trend = .03), and GPX1 rs1800668 (lower risk; P trend = .005). Toenail selenium levels were inversely associated with advanced PCa risk, independently of common genetic variation in SEPP1 and GPX1.

Pellatt AJ, Wolff RK, John EM, et al.
SEPP1 influences breast cancer risk among women with greater native american ancestry: the breast cancer health disparities study.
PLoS One. 2013; 8(11):e80554 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
Selenoproteins are a class of proteins containing a selenocysteine residue, many of which have been shown to have redox functions, acting as antioxidants to decrease oxidative stress. Selenoproteins have previously been associated with risk of various cancers and redox-related diseases. In this study we evaluated possible associations between breast cancer risk and survival and single nucleotide polymorphisms (SNPs) in the selenoprotein genes GPX1, GPX2, GPX3, GPX4, SELS, SEP15, SEPN1, SEPP1, SEPW1, TXNRD1, and TXNRD2 among Hispanic/Native American (2111 cases, 2597 controls) and non-Hispanic white (NHW) (1481 cases, 1586 controls) women in the Breast Cancer Health Disparities Study. Adaptive Rank Truncated Product (ARTP) analysis was used to determine both gene and pathway significance with these genes. The overall selenoprotein pathway PARTP was not significantly associated with breast cancer risk (PARTP = 0.69), and only one gene, GPX3, was of borderline significance for the overall population (PARTP =0.09) and marginally significant among women with 0-28% Native American (NA) ancestry (PARTP=0.06). The SEPP1 gene was statistically significantly associated with breast cancer risk among women with higher NA ancestry (PARTP=0.002) and contributed to a significant pathway among those women (PARTP=0.04). GPX1, GPX3, and SELS were associated with Estrogen Receptor-/Progesterone Receptor+ status (PARTP = 0.002, 0.05, and 0.01, respectively). Four SNPs (GPX3 rs2070593, rsGPX4 rs2074451, SELS rs9874, and TXNRD1 rs17202060) significantly interacted with dietary oxidative balance score after adjustment for multiple comparisons to alter breast cancer risk. GPX4 was significantly associated with breast cancer survival among those with the highest NA ancestry (PARTP = 0.05) only. Our data suggest that SEPP1 alters breast cancer risk among women with higher levels of NA ancestry.

Verschoor ML, Singh G
Ets-1 regulates intracellular glutathione levels: key target for resistant ovarian cancer.
Mol Cancer. 2013; 12(1):138 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
BACKGROUND: Ovarian cancer is characterized by high rates of metastasis and therapeutic resistance. Many chemotherapeutic agents rely on the induction of oxidative stress to cause cancer cell death, thus targeting redox regulation is a promising strategy to overcome drug resistance.
METHODS: We have used a tetracycline-inducible Ets-1 overexpression model derived from 2008 ovarian cancer cells in the present study. To examine the role of Ets-1 in glutathione regulation we have measured intracellular reactive oxygen species and glutathione levels, as well as glutathione peroxidase enzyme activity. Glutathione synthesis was limited using transsulfuration or Sx(c)- pathway blocking agents, and glutamate release was measured to confirm Sx(c)- blockade. Cell viability following drug treatment was assessed via crystal violet assay. Oxidative stress was induced through glucose oxidase treatment, which produces hydrogen peroxide by glucose oxidation. The protein expressions of redox-related factors were measured through western blotting.
RESULTS: Overexpression of Ets-1 was associated with decreased intracellular ROS, concomitantly with increased intracellular GSH, GPX antioxidant activity, and Sx(c)- transporter activity. Under basal conditions, inhibition of the transsulfuration pathway resulted in decreased GSH levels and GPX activity in all cell lines, whereas inhibition of Sx(c)- by sulfasalazine decreased GPX activity in Ets-1-expressing cells only. However, under oxidative stress the intracellular GSH levels decreased significantly in correlation with increased Ets-1 expression following sulfasalazine treatment.
CONCLUSIONS: In this study we have identified a role for proto-oncogene Ets-1 in the regulation of intracellular glutathione levels, and examined the effects of the anti-inflammatory drug sulfasalazine on glutathione depletion using an ovarian cancer cell model. The findings from this study show that Ets-1 mediates enhanced Sx(c)- activity to increase glutathione levels under oxidative stress, suggesting that Ets-1 could be a promising putative target to enhance conventional therapeutic strategies.

Aynali G, Doğan M, Sütcü R, et al.
Polymorphic variants of MnSOD Val16Ala, CAT-262 C < T and GPx1 Pro198Leu genotypes and the risk of laryngeal cancer in a smoking population.
J Laryngol Otol. 2013; 127(10):997-1000 [PubMed] Related Publications
OBJECTIVE: To investigate the relationship between development of laryngeal cancer and the presence of polymorphisms of the MnSOD Val16Ala, CAT-262 C < T and GPx1 Pro198Leu genes in a smoking population.
PATIENTS AND METHODS: Single nucleotide polymorphisms were determined in DNA from the peripheral blood erythrocytes of 48 heavy smokers (25 patients with laryngeal cancer and 23 cancer-free controls), using polymerase chain reaction.
RESULTS: There were no significant differences in age, smoking duration or smoking intensity, comparing the two groups. The homozygous AA genotype of MnSOD Val16Ala was significantly more prevalent in the cancer group than the control group (92 vs 13 per cent, respectively), while the heterozygous AV genotype of MnSOD Val16Ala was more prevalent in the control group than the cancer group (87 vs 8 per cent, respectively) (p < 0.001). There were no significant differences between the cancer and control groups regarding GPx1 Pro198Leu or CAT-262 C < T polymorphisms.
CONCLUSION: Polymorphism of the MnSOD Val16Ala gene may contribute to susceptibility to laryngeal cancer among smokers.

Méplan C, Dragsted LO, Ravn-Haren G, et al.
Association between polymorphisms in glutathione peroxidase and selenoprotein P genes, glutathione peroxidase activity, HRT use and breast cancer risk.
PLoS One. 2013; 8(9):e73316 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
Breast cancer (BC) is one of the most common cancers in women. Evidence suggests that genetic variation in antioxidant enzymes could influence BC risk, but to date the relationship between selenoproteins and BC risk remains unclear. In this report, a study population including 975 Danish cases and 975 controls matched for age and hormone replacement therapy (HRT) use was genotyped for five functional single nucleotide polymorphisms (SNPs) in SEPP1, GPX1, GPX4 and the antioxidant enzyme SOD2 genes. The influence of genetic polymorphisms on breast cancer risk was assessed using conditional logistic regression. Additionally pre-diagnosis erythrocyte GPx (eGPx) activity was measured in a sub-group of the population. A 60% reduction in risk of developing overall BC and ductal BC was observed in women who were homozygous Thr carriers for SEPP1 rs3877899. Additionally, Leu carriers for GPX1 Pro198Leu polymorphism (rs1050450) were at ∼2 fold increased risk of developing a non-ductal BC. Pre-diagnosis eGPx activity was found to depend on genotype for rs713041 (GPX4), rs3877899 (SEPP1), and rs1050450 (GPX1) and on HRT use. Moreover, depending on genotype and HRT use, eGPx activity was significantly lower in women who developed BC later in life compared with controls. Furthermore, GPx1 protein levels increased in human breast adenocarcinoma MCF7 cells exposed to β-estradiol and sodium selenite.In conclusion, our data provide evidence that SNPs in SEPP1 and GPX1 modulate risk of BC and that eGPx activity is modified by SNPs in SEPP1, GPX4 and GPX1 and by estrogens. Our data thus suggest a role of selenoproteins in BC development.

Cao M, Mu X, Jiang C, et al.
Single-nucleotide polymorphisms of GPX1 and MnSOD and susceptibility to bladder cancer: a systematic review and meta-analysis.
Tumour Biol. 2014; 35(1):759-64 [PubMed] Related Publications
Reactive oxygen species-related damage plays a critical role in carcinogenesis. Glutathione peroxidase 1 (GPX1) and mitochondrial superoxide dismutase (MnSOD) are two key antioxidant enzymes in the defense system against reactive oxygen species. This systematic review and meta-analysis was designed to evaluate the association of single-nucleotide polymorphisms in GPX1 and MnSOD genes with susceptibility to bladder cancer risk. Online databases of PubMed, Embase, China National Knowledge Infrastructure, and SinoMed were searched to identify eligible studies. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimated the association strength. The fixed effects model and random effects model were used to pool the data from different studies. By pooling all eligible studies, we found that the GPX1 Pro198Leu polymorphism was associated with a significantly increased risk of bladder cancer (Leu vs. Pro, OR = 2.111, 95% CI = 1.020-4.368, heterogeneity (p < 0.001); LeuPro/LeuLeu vs. ProPro, OR = 1.876, 95% CI = 1.011-3.480, heterogeneity (p < 0.001)). No significant association of MnSOD Ala-9Val polymorphism with cancer risk was observed (AlaVal/ValVal vs. AlaAla, OR = 0.966, 95% CI = 0.754-1.239, heterogeneity (p = 0.390); Vla vs. Ala, OR = 1.038, 95% CI = 0.782-1.377, heterogeneity (p = 0.015)). This systematic review and meta-analysis demonstrated that the GPX1 Pro198Leu polymorphism significantly increased susceptibility to bladder cancer, while the MnSOD Ala-9Val polymorphism was not associated with bladder cancer risk.

Men T, Zhang X, Yang J, et al.
The rs1050450 C > T polymorphism of GPX1 is associated with the risk of bladder but not prostate cancer: evidence from a meta-analysis.
Tumour Biol. 2014; 35(1):269-75 [PubMed] Related Publications
Glutathione peroxidase (GPX) is an endogenous antioxidant enzyme counteracting oxidative stress. Accumulating evidence has demonstrated that the GPX1 rs1050450 C > T polymorphism may modulate cancer risk, but the association of GPX1 rs1050450 polymorphism with bladder cancer (BC) and prostate cancer (PCa) is still inconclusive. This meta-analysis was designed to determine the exact association of GPX1 rs1050450 C > T polymorphism with the risk of bladder cancer and prostate cancer. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated to estimate the association strength. Databases of PubMed, EMBASE, and China National Knowledge Infrastructure were searched to retrieve eligible studies. In total, ten eligible studies with 6,194 participants were included. By pooling all eligible studies, we found that carriers of the variant T allele were associated with a significantly increased risk of urinary tract cancer (T vs. C: OR = 1.459 and 95% CI, 1.086-1.962; CT/TT vs. CC: OR = 1.411 and 95 % CI, 1.053-1.891). In stratified analysis, we observed that the rs1050450 C > T polymorphism was significantly associated with an increased risk of BC (T vs. C: OR = 2.111 and 95% CI, 1.020-4.368; CT/TT vs. CC: OR = 1.876 and 95% CI, 1.011-3.480), while the association was not significant for PCa. Egger's test and Begg's test revealed no publication bias. The present meta-analysis provides evidence that the GPX1 rs1050450 C > T polymorphism leads to an increased risk of BC but not the risk of PCa.

Jardim BV, Moschetta MG, Leonel C, et al.
Glutathione and glutathione peroxidase expression in breast cancer: an immunohistochemical and molecular study.
Oncol Rep. 2013; 30(3):1119-28 [PubMed] Related Publications
The use of prognostic markers for breast cancer allows therapeutic strategies to be defined more efficiently. The expression of glutathione (GSH) and glutathione peroxidase (GPX) in tumor cells has been evaluated as a predictor of prognosis and response to cytotoxic treatments. Its immunoexpression was assessed in 63 women diagnosed with invasive ductal carcinoma in a retrospective study. The results showed that high GSH expression was associated with tumors negative for the estrogen receptor (ER) (P<0.05), and GPX expression was associated with tumors negative for the progesterone receptor (PR) and patient mortality. Focusing on the 37 patients who received adjuvant chemotherapy/radiotherapy (Group I), high expression of GPX was associated with a high rate of patient mortality (P<0.05). The 19 patients who received only adjuvant chemotherapy (Group II) showed high expression of GSH in relation to metastasis (P<0.05). In addition, high levels of GPX expression were significantly associated with a shorter overall survival (P<0.05). To confirm this, the expression of precursor genes of GSH [glutamate cysteine ligase (GCLC) and glutathione synthetase (GSS)] and the GPX gene was analyzed using quantitative PCR in cultured neoplastic mammary cells treated with doxorubicin. Doxorubicin treatment was able to eliminate tumor cells without alterations in the gene expression of GSS, but led to underexpression of the GCLC and GPX genes. Our results suggest that high levels of GPX may be related to the development of resistance to chemotherapy in these tumors, response to treatment and the clinical course of the breast cancer patients.

Okubo T, Saito T, Mitomi H, et al.
p53 mutations may be involved in malignant transformation of giant cell tumor of bone through interaction with GPX1.
Virchows Arch. 2013; 463(1):67-77 [PubMed] Related Publications
Giant cell tumor of bone (GCTB) is a benign tumor with a tendency for local recurrence. Secondary malignant GCTB is rare, occurring in less than 2 % of GCTB cases. Mechanisms of malignant transformation of GCTB remain unclear. We examined 43 cases of GCTB (38 conventional cases, two lung implantation cases, and three secondary malignant cases) for p53 gene mutations and for loss of heterozygosity (LOH) of p53 when corresponding normal tissue was available. In addition, to elucidate the possible involvement of p53, GPX-1, cyclinD1, and Ki-67 in malignant transformation of GCTB, we assessed the expression of these proteins by immunohistochemistry. Mutations or LOH of p53 were found in all three malignant cases, which also showed p53 overexpression. Non-synonymous p53 mutations were detected in seven of 38 conventional cases (18 %), although none of these showed p53 overexpression, defined as more than 10 % of cells being positive. LOH at the p53 locus was detected in eight of 37 informative cases, although this was not associated with p53 overexpression in conventional GCT. Expression of GPX-1 was higher in the recurrent group, which included metastatic and malignant cases, and patients with high GPX-1 expression were at greater risk for early relapse. We also observed a positive correlation between high p53 expression and high GPX-1 expression in GCTB. Given that GPX-1 is shown to be a target of p53, these results suggest that p53 mutations play a role in tumor recurrence and malignant transformation of GCTB through interactions with GPX-1.

Jaworska K, Gupta S, Durda K, et al.
A low selenium level is associated with lung and laryngeal cancers.
PLoS One. 2013; 8(3):e59051 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
PURPOSE: It has been suggested that selenium deficiency is a risk factor for several cancer types. We conducted a case-control study in Szczecin, a region of northwestern Poland, on 95 cases of lung cancer, 113 cases of laryngeal cancer and corresponding healthy controls.
METHODS: We measured the serum level of selenium and established genotypes for four variants in four selenoprotein genes (GPX1, GPX4, TXNRD2 and SEP15). Selenium levels in the cases were measured after diagnosis but before treatment. We calculated the odds of being diagnosed with lung or laryngeal cancer, conditional on selenium level and genotype.
RESULTS: Among lung cancer cases, the mean selenium level was 63.2 µg/l, compared to a mean level of 74.6 µg/l for their matched controls (p<0.0001). Among laryngeal cancer cases, the mean selenium level was 64.8 µg/l, compared to a mean level of 77.1 µg/l for their matched controls (p<0.0001). Compared to a serum selenium value below 60 µg/l, a selenium level above 80 µg/l was associated with an odds ratio of 0.10 (95% CI 0.03 to 0.34; p = 0.0002) for lung cancer and 0.23 (95% CI 0. 09 to 0.56; p = 0.001) for laryngeal cancer. In analysis of four selenoprotein genes we found a modest evidence of association of genetic variant in GPX1 with the risk of lung and laryngeal cancers.
CONCLUSION: A selenium level below 60 µg/l is associated with a high risk of both lung and laryngeal cancer.

Seibold P, Hall P, Schoof N, et al.
Polymorphisms in oxidative stress-related genes and mortality in breast cancer patients--potential differential effects by radiotherapy?
Breast. 2013; 22(5):817-23 [PubMed] Related Publications
We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A, NFE2L2, NQO1, PRDX1, and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HRNQO1_rs2917667 1.20, 95% CI 1.00-1.44, p = 0.051; HRPRDX6_rs7314 1.16, 95% CI 1.00-1.35, p = 0.056, HRPRDX6_rs4916362 1.14 95% CI 1.00-1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT_rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.

Karunasinghe N, Han DY, Goudie M, et al.
Prostate disease risk factors among a New Zealand cohort.
J Nutrigenet Nutrigenomics. 2012; 5(6):339-51 [PubMed] Related Publications
BACKGROUND: Prostate cancer is a leading public health burden worldwide, and in New Zealand it is the most commonly registered cancer and the third leading cause of cancer deaths among males. Genetic variability and its associations with diet, demographic and lifestyle factors could influence the risk of this disease.
METHODS: The single nucleotide polymorphisms (SNPs) within a group of antioxidant genes and related markers were tested between patient and control cohorts, adjusted for significant differences between basic lifestyle and demographic characteristics.
RESULTS: Increasing age, smoking and low serum selenium levels were significantly associated with an increased risk for prostate disease. Alcohol consumption increased the glutathione peroxidase (GPx) activity. A significant reduction in alcohol consumption was recorded with prostate disease. Three SNPs, namely GPx1 rs1050450, SEL15 rs5845 and CAT rs1001179, were significantly associated with prostate disease risk. A cumulative risk of prostate cancer was noted with 6 risk alleles. A lower GPx activity was recorded with prostate disease compared to the controls. However, the GPx1 rs1050450 allele T in association with prostate cancer recorded a significantly higher GPx activity compared to the controls.
CONCLUSIONS: These data point to a possibility of identifying individuals at risk of prostate cancer for better management purposes.

Zhao P, Zhao L, Zou P, et al.
Genetic oxidative stress variants and glioma risk in a Chinese population: a hospital-based case-control study.
BMC Cancer. 2012; 12:617 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
BACKGROUND: The oxidative stress mechanism is of particular interest in the pathogenesis of glioma, given the high rate of oxygen metabolism in the brain. Potential links between polymorphisms of antioxidant genes and glioma risk are currently unknown. We therefore investigated the association between polymorphisms in antioxidant genes and glioma risk.
METHODS: We examined 16 single nucleotide polymorphisms (SNPs) of 9 antioxidant genes (GPX1, CAT, PON1, NQO1, SOD2/MnSOD, SOD3, and NOS1*2*3) in 384 glioma and 384 control cases in a Chinese hospital-based case-control study. Genotypes were determined using the OpenArray platform, which employs the chip-based Taq-Man genotyping technology. The adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using unconditional logistic regression.
RESULTS: Using single-locus analysis, we identified four SNPs (SOD2 V16A, SOD3 T58A, GPX1 -46 C/T, and NOS1 3'-UTR) that were significantly associated with the risk of glioma development. To assess the cumulative effects, we performed a combined unfavourable genotype analysis. Compared with the reference group that exhibited no unfavourable genotypes, the medium- and high-risk groups exhibited a 1.86-fold (95% CI, 1.30-2.67) and a 4.86-fold (95% CI, 1.33-17.71) increased risk of glioma, respectively (P-value for the trend < 0.001).
CONCLUSIONS: These data suggest that genetic variations in oxidative stress genes might contribute to the aetiology of glioma.

Geybels MS, Hutter CM, Kwon EM, et al.
Variation in selenoenzyme genes and prostate cancer risk and survival.
Prostate. 2013; 73(7):734-42 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
BACKGROUND: While several studies showed that selenium may prevent prostate cancer (PCa), few studies have evaluated variation in selenoenzyme genes in relation to PCa risk and survival.
METHODS: We studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). In a population-based case-control study of men of European ancestry (1,309 cases, 1,266 controls), we evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n = 2), GPX2 (n = 4), GPX3 (n = 6), GPX4 (n = 6), SEP15 (n = 4), SEPP1 (n = 6), and TXNRD1 (n = 7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. We used logistic regression and Cox proportional hazards regression to estimate the relative risk of PCa and PCSM, respectively.
RESULTS: Of the SNPs examined, only GPX1 rs3448 was associated with overall PCa risk with an odds ratio of 0.62 for TT versus CC (95% confidence interval, 0.44-0.88). SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade. We observed associations between SNPs in GPX4, and TXNRD1 and risk of PCSM. None of these associations, however, remained significant after adjustment for multiple comparisons.
CONCLUSIONS: We found evidence that genetic variation in a subset of selenoenzyme genes may alter risk of PCa and PCSM. These results need validation in additional subsets.

Hong Z, Tian C, Zhang X
GPX1 gene Pro200Leu polymorphism, erythrocyte GPX activity, and cancer risk.
Mol Biol Rep. 2013; 40(2):1801-12 [PubMed] Related Publications
A meta-analysis was conducted to assess the effect of glutathione peroxidase1 (GPX1) gene Pro200Leu (rs1050450) polymorphism on cancer risk. A comprehensive search was performed to identify all studies on the association of GPX1 gene Pro200Leu polymorphism with cancer risk. The fixed or random effect pooled measure was selected based on homogeneity test among studies. Heterogeneity among studies was evaluated using the I (2). Potential sources of between-study heterogeneity were explored by meta-regression and the sensitivity analysis. Publication bias was estimated using Egger's linear regression test. 35 published articles with 36 results were identified involving 16,920 cases and 19,946 controls. Results from the articles that both obeyed Hardy-Weinberg equilibrium in controls and met high quality design, showed no significant association of GPX1 gene Pro200Leu polymorphism with cancer risk in any of dominant (OR = 1.05, 95 %CI = 0.98-1.12), recessive (OR = 1.04 (0.95-1.13), and TT versus CC (OR = 1.05, 95 %CI = 0.97-1.15) models, and the findings were consistent considering the stratified analysis by cancer type. However, multivariate-adjusted ORs from articles that both obeyed Hardy-Weinberg equilibrium in controls and met high quality design, showed a significant association considering dominant (OR = 1.22, 95 %CI = 1.06-1.41), TT versus CC (OR = 1.16, 95 %CI = 1.02-1.32) models, and a marginally significant association was found considering TC versus CC (OR = 1.11, 95 %CI = 0.99-1.25) model. And compared with the CC genotype, the erythrocyte GPX activity was significantly lower for TT genotype: the standardized mean difference (SMD) = -0.37, 95 %CI = (-0.624, -0.118), and CT genotype: SMD = -0.19, 95 %CI = (-0.37, -0.002). The association of GPX1 gene Pro200Leu polymorphism with cancer risk might be influenced by confounders.

Giesing M, Driesel G, Molitor D, Suchy B
Molecular phenotyping of circulating tumour cells in patients with prostate cancer: prediction of distant metastases.
BJU Int. 2012; 110(11 Pt C):E1202-11 [PubMed] Related Publications
UNLABELLED: What's known on the subject? and What does the study add? The role of circulating cancer cells in metastogenesis is generally accepted. Two forms of these cells have been reported in a number of studies, cancer cell clusters (CCCs) and individual epithelial cancer cells. Clusters appear at higher frequencies in the blood. CCCs have been reported to be rich in vimentin and poor in E-cadherin expression The resulting epithelial to mesenchymal transition, a prerequisite for metastasis formation, occurs in CCCs. We have developed a new set of biomarkers, namely the antioxidant genes GPX1, SOD2 and TXNRD1, specific to cell trafficking in the blood. Firstly, the study shows that diagnosis of distant metastases is feasible by applying molecular phenotyping with a five gene test that has 94% sensitivity and 81% accuracy. Again SOD2 and GPX1 showed the highest sensitivities. Secondly, the study shows the efficacy of palliative chemotherapy in clearing the blood of CCCs overexpressing diagnostic genes. Clinically the overall lifespan ranged from 5 to 99 months under taxotere. We aimed to investigate the molecular reasons and found that MDR1 overexpression worsened survival by 31%. To the best of our knowledge, this is the first study to show the clinical impact of drug targeting and the counter-effect of drug resistance in CCCs on overall survival. The findings may, therefore, add a novel tool for clinicians in tailoring therapies individually.
OBJECTIVES: • To find the molecular phenotype in circulating cancer cells from patients with prostate cancer (PCa) in order to predict distant metastases. • To determine genes affecting the study endpoints of overall survival and time to progression.
PATIENTS AND METHODS: • Twenty-five urologists in several clinics participated in the study, with 51 patients with metastatic and 77 with non-metastatic PCa. • Molecular analysis was carried out in two forms of circulating cancer cells, cancer cell clusters (CCCs) and individual epithelial cancer cells (CECs). • Gene expression was studied using real-time reverse-transcriptase PCR. • Cycle threshold values were normalized with glyceraldehyde 3-phosphate dehydrogenase in cancer cells and mononucleated cells, yielding comparative specific expression values from the relative quantification method with the help of the standard curve method for each patient and each gene locus.
RESULTS: • Preclinical validation was performed using aggregated and non-aggregated SW480 cells showing the independence of CCCs and CECs. • Prediction of metastases was achieved with five genes showing the highest sensitivity, SOD2, GPX1, AR, cyclin B and bFGF. • The following results were obtained: 94% sensitivity, 65% specificity, 76% positive predictive value and 89% negative predictive value. The prevalence was 63%. Test accuracy was 81% with an odds ratio of 32 (P < 0.001). • Overall survival was worsened by preceding chemotherapies when leaving insufficient GPX1 clearance in blood. • Drug resistance genes were found to worsen the endpoints, among them MDR1 (P = 0.003; hazard ratio: 1.31; 95% CI: 1.09-1.58).
CONCLUSIONS: • SOD2, GPX1 and AR represent a novel biomarker set for circulating cancer cells (clusters and scattered individual cells) in PCa. • The clinical usefulness of these biomarkers ranges from the prediction of clinical tumours to disease prognostication, therapy monitoring and therapy outcome prediction (hormonal therapies, chemotherapies). • The presence of CCCs and CECs after batch isolation allows the addition of genes for intensive studies, e.g. drug resistance.

Beane J, Cheng L, Soldi R, et al.
SIRT1 pathway dysregulation in the smoke-exposed airway epithelium and lung tumor tissue.
Cancer Res. 2012; 72(22):5702-11 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
Cigarette smoke produces a molecular field of injury in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco exposure, including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly upregulated in cytologically normal bronchial airway epithelial cells from active smokers compared with nonsmokers. In contrast, this activity is strikingly downregulated in non-small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and downregulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Furthermore, our findings suggest that the airway gene expression signatures derived in this study can provide novel insights into signaling pathways altered in the "field of injury" induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer.

Okuno T, Miura K, Sakazaki F, et al.
Methylseleninic acid (MSA) inhibits 17β-estradiol-induced cell growth in breast cancer T47D cells via enhancement of the antioxidative thioredoxin/ thioredoxin reductase system.
Biomed Res. 2012; 33(4):201-10 [PubMed] Related Publications
The purpose of this study was to clarify the cell growth inhibitory mechanism of human breast cancer cells caused by selenium (Se) compounds. In the presence of 17β-estradiol (E(2)) at physiological concentrations, growth of estrogen receptor α (ERα)-positive T47D cells was markedly inhibited by 1 × 10(-6) mol/L methylseleninic acid (MSA) with no Se related toxicity.Under conditions where cell growth was inhibited, MSA decreased ERα mRNA levels and subsequent protein levels; further decreasing expression of estrogen-responsive finger protein (Efp) which is a target gene product of ERα and promotes G2/M progression of the cell cycle. Therefore, the decline in Efp expression is presumed to be involved in G2 arrest. Coincidentally, the antioxidative thioredoxin/ thioredoxin reductase (Trx/TrxR) system in cells was enhanced by the synergistic action of E(2) and MSA. It has been reported that ROS-induced oxidative stress enhanced ERα expression. E(2) increased production of intracellular ROS in T47D cells. Meanwhile, MSA significantly decreased E(2)-induced ROS accumulation. From these results, activation of the Trx/TrxR system induced by the coexistence of MSA and E(2) suppresses oxidative stress and decreases expression of ERα, and finally induces the growth arrest of T47D cells through disruption of ERα signaling.

Kulak MV, Cyr AR, Woodfield GW, et al.
Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer.
Oncogene. 2013; 32(34):4043-51 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
The complexity of gene regulation has created obstacles to defining mechanisms that establish the patterns of gene expression characteristic of the different clinical phenotypes of breast cancer. TFAP2C is a transcription factor that has a critical role in the regulation of both estrogen receptor-alpha (ERα) and c-ErbB2/HER2 (Her2). Herein, we performed chromatin immunoprecipitation and direct sequencing (ChIP-seq) for TFAP2C in four breast cancer cell lines. Comparing the genomic binding sites for TFAP2C, we identified that glutathione peroxidase (GPX1) is regulated by TFAP2C through an AP-2 regulatory region in the promoter of the GPX1 gene. Knockdown of TFAP2C, but not the related factor TFAP2A, resulted in an abrogation of GPX1 expression. Selenium-dependent GPX activity correlated with endogenous GPX1 expression and overexpression of exogenous GPX1 induced GPX activity and significantly increased resistance to tert-butyl hydroperoxide. Methylation of the CpG island encompassing the AP-2 regulatory region was identified in cell lines where TFAP2C failed to bind the GPX1 promoter and GPX1 expression was unresponsive to TFAP2C. Furthermore, in cell lines where GPX1 promoter methylation was associated with gene silencing, treatment with 5'-aza-2-deoxycytidine (5'-aza-dC) (an inhibitor of DNA methylation) allowed TFAP2C to bind to the GPX1 promoter resulting in the activation of GPX1 RNA and protein expression. Methylation of the GPX1 promoter was identified in ∼20% of primary breast cancers and a highly significant correlation between the TFAP2C and GPX1 expression was confirmed when considering only those tumors with an unmethylated promoter, whereas the related factor, TFAP2A, failed to demonstrate a correlation. The results demonstrate that TFAP2C regulates the expression of GPX1, which influences the redox state and sensitivity to oxidative stress induced by peroxides. Given the established role of GPX1 in breast cancer, the results provide an important mechanism for TFAP2C to further influence oncogenesis and progression of breast carcinoma cells.

Dluzniewski PJ, Wang MH, Zheng SL, et al.
Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.
Cancer Epidemiol Biomarkers Prev. 2012; 21(10):1774-82 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
BACKGROUND: To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer.
METHODS: We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI).
RESULTS: The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00-3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48-0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence.
CONCLUSION: Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors.
IMPACT: This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis.

Min SY, Kim HS, Jung EJ, et al.
Prognostic significance of glutathione peroxidase 1 (GPX1) down-regulation and correlation with aberrant promoter methylation in human gastric cancer.
Anticancer Res. 2012; 32(8):3169-75 [PubMed] Related Publications
BACKGROUND: This study aimed at examining the association of gene silencing and promoter methylation of glutathione peroxidase 1 (GPX1) and glutathione peroxidase 3 (GPX3) in gastric cancer cells and determined the clinical significance of GPX1 and GPX3 expression loss in gastric cancer tissue.
MATERIALS AND METHODS: Analysis of mRNA expression was carried out by reverse transcription-polymerase chain reaction (RT-PCR). Methylation of the GPX1 promoter region was analyzed by bisulfite sequencing, and that of the GPX3 promoter region was analyzed by methylation-specific PCR (MSP). Tissue microarray-based immunohistochemistry of GPX1 and GPX3 in 1,163 resected gastric cancer specimens was performed to assess the associations with clinicopathological parameters.
RESULTS: Reduced GPX1 and GPX3 mRNA expression was associated with promoter methylation in gastric cancer cell lines. A correlation between DNA promoter methylation and loss of GPX1 expression was noted in 16 gastric cancer tissue samples (p=0.005). Loss of GPX1 and GPX3 proteins was found in 24.4% and 30.8% of gastric cancer tissues. Loss of GPX1 expression was significantly associated with advanced gastric cancer (p=0.039) and lymphatic invasion (p=0.010); loss of GPX3 expression was associated with advanced gastric cancer (p<0.001) and lymph node metastasis (p<0.001). Kaplan-Meier analysis showed that low expression of GPX1 was associated with poor cancer-specific survival (p=0.010).
CONCLUSION: Data from this study implicate aberrant hypermethylation of promoter regions of GPX1 and GPX3 as a mechanism for down-regulation of GPX1 and GPX3 mRNA expression in gastric cancer cells. Loss of GPX1 expression was associated with aggressiveness and poor survival in patients with gastric cancer.

Liwei L, Wei Z, Ruifa H, Chunyu L
Association between genetic variants in glutathione peroxidase 1 gene and risk of prostate cancer: a meta-analysis.
Mol Biol Rep. 2012; 39(9):8615-9 [PubMed] Related Publications
To examine the association between glutathione peroxidase 1 (GPx1) gene Pro198Leu polymorphism with the development and progression of prostate cancer. A comprehensive search was conducted to identify all case-control studies of GPx1 polymorphisms and prostate cancer. Statistical analysis was performed with the software program Stata, version 11.0, and Review Manage, version 4.2. A total of 7 eligible studies relating the GPx1 polymorphism to the risk of prostate cancer were identified. The results indicated no significant association between GPx1 polymorphisms and prostate cancer susceptibility in the dominant model (random effects OR 0.75, 95 % CI 0.48-1.18), recessive model (random effects OR 0.47, 95 % CI 0.22-1.01) and co-dominant genetic model (random effects OR 0.72, 95 % CI 0.43-1.21). For the analysis of GPx1 polymorphism and progression of prostate cancer, no significant association were found in the dominant model (fixed effects OR 1.20, 95 % CI 0.95-1.52), recessive model (fixed effects OR 0.69, 95 % CI 0.48-1.00) and co-dominant genetic model (fixed effects OR 0.95, 95 % CI 0.79-1.15). Egger's test showed that publication bias was not present in all the comparisons.

Brackett J, Krull KR, Scheurer ME, et al.
Antioxidant enzyme polymorphisms and neuropsychological outcomes in medulloblastoma survivors: a report from the Childhood Cancer Survivor Study.
Neuro Oncol. 2012; 14(8):1018-25 [PubMed] Article available free on PMC after 21/08/2015 Related Publications
Psychological or neurocognitive impairment is often seen in medulloblastoma survivors after craniospinal radiation; however, significant variability in outcomes exists. This study investigated the role of antioxidant enzyme polymorphisms in moderating this outcome and hypothesized that patients who had polymorphisms associated with lower antioxidant enzyme function would have a higher occurrence of impairment. From the Childhood Cancer Survivor Study (CCSS) cohort, 109 medulloblastoma survivors and 143 siblings were identified who completed the CCSS Neurocognitive Questionnaire (NCQ) and the Brief Symptom Inventory-18 (BSI-18) and who provided buccal DNA samples. Real-time polymerase chain reaction (PCR) allelic discrimination was used for SOD2 (rs4880), GPX1 (rs1050450), and GSTP1 (rs1695 and rs1138272) genotyping and PCR for GSTM1 and GSTT1 gene deletions. Outcomes on NCQ and BSI-18 subscale scores were examined in association with genotypes and clinical factors, including age at diagnosis, sex, and radiation dose, using univariate and multivariate analysis of variance. Patients <7 years of age at diagnosis displayed more problems with task efficiency (P < .001) and fewer problems with somatic complaints (P = .004) than did patients ≥7 years of age. Female patients reported more organization problems than did male patients (P = .02). Patients with homozygous GSTM1 gene deletion reported higher anxiety (mean null genotype = 47.3 ± 9.2, non-null = 43.9 ± 7.8; P = .04), more depression (null = 51.0 ± 9.8, non-null = 47.0 ± 9.4; P = .03), and more global distress (null = 50.2 ± 9.7, non-null = 45.2 ± 9.9; P = .01). All associations for the GSTM1 polymorphism remained statistically significant in a multivariate model controlling for age, sex, and radiation dose. Homozygous GSTM1 gene deletion was consistently associated with greater psychological distress in medulloblastoma survivors across multiple domains, suggesting that this genotype may predispose patients for increased emotional late effects.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. GPX1, Cancer Genetics Web: http://www.cancer-genetics.org/GPX1.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 06 August, 2015     Cancer Genetics Web, Established 1999