GPX3

Gene Summary

Gene:GPX3; glutathione peroxidase 3
Aliases: GPx-P, GSHPx-3, GSHPx-P
Location:5q33.1
Summary:The protein encoded by this gene belongs to the glutathione peroxidase family, members of which catalyze the reduction of organic hydroperoxides and hydrogen peroxide (H2O2) by glutathione, and thereby protect cells against oxidative damage. Several isozymes of this gene family exist in vertebrates, which vary in cellular location and substrate specificity. This isozyme is secreted, and is abundantly found in plasma. Downregulation of expression of this gene by promoter hypermethylation has been observed in a wide spectrum of human malignancies, including thyroid cancer, hepatocellular carcinoma and chronic myeloid leukemia. This isozyme is also a selenoprotein, containing the rare amino acid selenocysteine (Sec) at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2016]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:glutathione peroxidase 3
Source:NCBIAccessed: 16 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 16 March 2017 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.

  • Down-Regulation
  • DNA Methylation
  • GPX3
  • Adenocarcinoma
  • Transcriptional Activation
  • Gene Expression Profiling
  • Survival Rate
  • Azacitidine
  • Thyroid Cancer
  • Case-Control Studies
  • RTPCR
  • Thioredoxin Reductase 1
  • Epigenetics
  • Risk Factors
  • Stomach Cancer
  • Surveys and Questionnaires
  • Selenoproteins
  • Biomarkers, Tumor
  • Prostate Cancer
  • Gene Silencing
  • Genetic Predisposition
  • Genotype
  • Glutathione Peroxidase
  • Up-Regulation
  • Ultraviolet Rays
  • Oligonucleotide Array Sequence Analysis
  • Uterine Myomectomy
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Tumor Suppressor Proteins
  • Serum Amyloid P-Component
  • Taiwan
  • Research Design
  • Selenium
  • Enzymologic Gene Expression Regulation
  • Chromosome 5
  • Cancer Gene Expression Regulation
  • Esophageal Cancer
  • Single Nucleotide Polymorphism
  • Transcription Factors
  • Promoter Regions
  • Thiazolidinediones
  • beta Catenin
  • CpG Islands
Tag cloud generated 16 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: GPX3 (cancer-related)

Wieczorek E, Jablonowski Z, Tomasik B, et al.
Different Gene Expression and Activity Pattern of Antioxidant Enzymes in Bladder Cancer.
Anticancer Res. 2017; 37(2):841-848 [PubMed] Related Publications
The aim of this study was to evaluate the possible role in and contribution of antioxidant enzymes to bladder cancer (BC) etiology and recurrence after transurethral resection (TUR). We enrolled 40 patients with BC who underwent TUR and 100 sex- and age-matched healthy controls. The analysis was performed at diagnosis and recurrence, taking into account the time of recurrence. Gene expression of catalase (CAT), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (SOD2) was determined in peripheral blood leukocytes. The activity of glutathione peroxidase 3 (GPX3) was examined in plasma, and GPX1 and copper-zinc containing superoxide dismutase 1 (SOD1) in erythrocytes. SOD2 and GPX1 expression and GPX1 and SOD1 activity were significantly higher in patients at diagnosis of BC in comparison to controls. In patients who had recurrence earlier than 1 year from TUR, CAT and SOD2 expression was lower (at diagnosis p=0.024 and p=0.434, at recurrence p=0.022 and p=0.010), while the GPX1 and GPX3 activity was higher (at diagnosis p=0.242 and p=0.394, at recurrence p=0.019 and p=0.025) compared to patients with recurrence after 1 year from TUR. This study revealed that the gene expression and activity of the antioxidant enzymes are elevated in blood of patients with BC, although a low expression of CAT might contribute to the recurrence of BC, in early prognosis.

Chen H, Zheng Z, Kim KY, et al.
Hypermethylation and downregulation of glutathione peroxidase 3 are related to pathogenesis of melanoma.
Oncol Rep. 2016; 36(5):2737-2744 [PubMed] Related Publications
As a crucial antioxidant enzyme, glutathione peroxidase 3 (GPX3) has been found to be frequently repressed in many cancers due to promoter hypermethylation and is known as a possible tumor suppressor gene. In the present study, we investigated whether promoter hypermethylation of GPX3 and its repression are present in melanoma and, if so, whether GPX3 downregulation is implicated in the pathogenesis of melanoma. Our results revealed methylation of GPX3 and downregulation of its expression in both melanoma cell lines and surgical melanoma tissue samples. In melanoma cell lines, GPX3 expression was restored by treatment with 5-aza-2'-deoxycytidine both in mRNA and protein levels. Depletion of GPX3 was found to increase the proliferative ability, motility, and invasiveness of melanoma cells. Moreover, negative expression of GPX3 was related to poor prognosis in melanoma patients. These results suggest that methylation-mediated GPX3 repression may have critical implications for melanoma pathogenesis.

Xie W, Yang M, Chan J, et al.
Association of genetic variations of selenoprotein genes, plasma selenium levels, and prostate cancer aggressiveness at diagnosis.
Prostate. 2016; 76(7):691-9 [PubMed] Related Publications
BACKGROUND: Genetic variations in some of the selenoprotein genes, alone or together with an individual's selenium status, may influence risk or progression of prostate cancer. We investigated the impact of genetic variants of selenoproteins on plasma selenium levels and cancer aggressiveness at diagnosis in men with localized prostate cancer (PCa).
METHODS: The study cohort comprised 722 patients seen at Dana-Farber Cancer Institute who had localized/locally advanced PCa (i.e., stage T3 or less, N0, and M0) from 1994 to 2001. Fifty-five tagging single nucleotide polymorphisms (SNPs) from six selenoprotein genes (TXNRD1, TXNRD2, SEP15, GPX3, SELENBP1, and SEPP1) were analyzed. Logistic regression is used to examine associations of genotypes and plasma selenium levels with risk of aggressive disease, defined as D'Amico intermediate/high risk categories. Step down permutation was applied to adjust for multiple comparisons.
RESULTS: Three hundred and forty-eight patients (48%) had aggressive disease at diagnosis. Two SNPs were associated with cancer aggressiveness at diagnosis (unadjusted P = 0.017 and 0.018, respectively). The odds ratio for aggressive disease in patients carrying TXNRD2 rs1005873-AG/GG genotypes or SELENBP1 rs10788804-AG/AA genotypes was 1.54 (95% CI = 1.08, 2.20) and 1.45 (95% CI = 1.07, 1.98), respectively, compared to TXNRD2 rs1005873-AA or SELENBP1 rs10788804-GG carriers. Four SNPs in TXNRD2 (rs1005873, rs13054371, rs3788310, and rs9606174) and the rs230820 in SEPP1 were associated with plasma selenium levels (unadjusted P < 0.05). Permutation adjusted P-values were not statistically significant for all these comparisons at the cut-off point of 0.05.
CONCLUSION: We identified polymorphisms in selenoproteins that may influence the plasma selenium levels and may be associated with the risk of presenting with aggressive PCa in men with localized or locally advanced PCa. These results should be validated in other independent datasets.

Zmorzyński S, Świderska-Kołacz G, Koczkodaj D, Filip AA
Significance of Polymorphisms and Expression of Enzyme-Encoding Genes Related to Glutathione in Hematopoietic Cancers and Solid Tumors.
Biomed Res Int. 2015; 2015:853573 [PubMed] Free Access to Full Article Related Publications
Antioxidant compounds such as glutathione and its enzymes have become the focus of attention of medical sciences. Glutathione, a specific tripeptide, is involved in many intercellular processes. The glutathione concentration is determined by the number of GAG repeats in gamma-glutamylcysteine synthetase. GAG polymorphisms are associated with an increased risk of schizophrenia, berylliosis, diabetes, lung cancer, and nasopharyngeal tumors. Cancer cells with high glutathione concentration are resistant to chemotherapy treatment. The oxidized form of glutathione is formed by glutathione peroxidases (GPXs). The changes in activity of GPX1, GPX2, and GPX3 isoforms may be associated with the development of cancers, for example, prostate cancer or even colon cancer. Detoxification of glutathione conjugates is possible due to activity of glutathione S-transferases (GSTs). Polymorphisms in GSTM1, GSTP1, and GSTO1 enzymes increase the risk of developing breast cancer and hepatocellular carcinoma. Gamma-glutamyl transpeptidases (GGTs) are responsible for glutathione degradation. Increased activity of GGT correlates with adverse prognosis in patients with breast cancer. Studies on genes encoding glutathione enzymes are continued in order to determine the correlation between DNA polymorphisms in cancer patients.

Jablonska E, Gromadzinska J, Peplonska B, et al.
Lipid peroxidation and glutathione peroxidase activity relationship in breast cancer depends on functional polymorphism of GPX1.
BMC Cancer. 2015; 15:657 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Since targeting oxidative stress markers has been recently recognized as a novel therapeutic target in cancer, it is interesting to investigate whether genetic susceptibility may modify oxidative stress response in cancer. The aim of this study was to elucidate whether genetic polymorphism in the antioxidant enzymes is associated with lipid peroxidation in breast cancer.
METHODS: We conducted a study among Polish women, including 136 breast cancer cases and 183 healthy controls. The analysis included genetic polymorphisms in five redox related genes: GPX1 (rs1050450), GPX4 (rs713041), SOD2 (rs4880), SEPP1 (rs3877899) and SEP15 (rs5859), lipid peroxidation, the activities of antioxidant enzymes determined in blood compartments as well as plasma concentration of selenium - an antioxidant trace element involved in cancer. Genotyping was performed using the Real Time PCR. Lipid peroxidation was expressed as plasma concentration of thiobarbituric acid reactive substances (TBARS) and measured with the spectrofluorometric method. Glutathione peroxidase activity was spectrophotometrically determined in erythrocytes (GPx1) and plasma (GPx3) by the use of Paglia and Valentine method. Spectrophotometric methods were employed to measure activity of cytosolic superoxide dismutase (SOD1) in erythrocytes (Beauchamp and Fridovich method) and ceruloplasmin (Cp) in plasma (Sunderman and Nomoto method). Plasma selenium concentration was determined using graphite furnace atomic absorption spectrophotometry.
RESULTS: Breast cancer risk was significantly associated with GPX1 rs1050450 (Pro198Leu) polymorphism, showing a protective effect of variant (Leu) allele. As compared to the control subjects, lipid peroxidation and GPx1 activity were significantly higher in the breast cancer cases, whereas ceruloplasmin activity was decreased. After genotype stratification, both GPx1 activity and TBARS concentration were the highest in GPX1 Pro/Pro homozygotes affected by breast cancer. At the same time, there was a significant correlation between the level of lipid peroxidation and GPx1 activity among the cancer subjects possessing GPX1 Pro/Pro genotype (r = 0.3043; p = 0.0089), whereas such a correlation was completely absent in the cases carrying at least one GPX1 Leu allele as well as in the controls (regardless of GPX1 genotype).
CONCLUSIONS: GPX1 polymorphism may be an important factor modifying oxidative stress response in breast cancer subjects. Further studies are needed to elucidate its potential clinical significance.

Lee CH, Pan KL, Tang YC, et al.
LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation.
Oncotarget. 2015; 6(28):25188-201 [PubMed] Free Access to Full Article Related Publications
Previously, we identified global epigenetic aberrations in smoking-associated oral squamous cell carcinoma (OSCC). We hypothesized that cigarette exposure triggers OSCC through alteration of the methylome of oral cells. Here we report that cigarette smoke condensate (CSC) significantly changes the genomic 5-methyldeoxycytidine content and nuclear accumulation of DNA methyltransferase 1 (DNMT1) and DNMT3A in human untransformed oral cells. By using integrated analysis of cDNA and methylation arrays of the smoking-associated dysplastic oral cell line and OSCC tumors, respectively, we identified four epigenetic targets--UCHL1, GPX3, LXN, and LDOC1--which may be silenced by cigarette. Results of quantitative methylation-specific PCR showed that among these four genes, LDOC1 promoter was the most sensitive to CSC. LDOC1 promoter hypermethylation and gene silencing followed 3 weeks of CSC treatment. LDOC1 knockdown led to a proliferative response and acquired clonogenicity of untransformed oral cells. Immunohistochemistry showed that LDOC1 was downregulated in 53.3% (8/15) and 57.1% (20/35) of premalignant oral tissues and early stage OSCCs, respectively, whereas 76.5% (13/17) of normal oral tissues showed high LDOC1 expression. Furthermore, the microarray data showed that LDOC1 expression had decreased in the lung tissues of current smokers compared with that in those of never smokers and had significantly decreased in the lung tumors of smokers compared with that in normal lung tissues. Our data suggest that CSC-induced promoter methylation may contribute to LDOC1 downregulation, thereby conferring oncogenic features to oral cells. These findings also imply a tumor suppressor role of LDOC1 in smoking-related malignancies such as OSCC and lung cancer.

Yao DM, Zhou JD, Zhang YY, et al.
GPX3 promoter is methylated in chronic myeloid leukemia.
Int J Clin Exp Pathol. 2015; 8(6):6450-7 [PubMed] Free Access to Full Article Related Publications
Hypermethylation of GPX3 (glutathione peroxidase 3) promoter has been identified in various cancers. However, the pattern of GPX3 promoter methylation in chronic myeloid leukemia (CML) remains unknown. Our study was aimed to investigate the methylation status of GPX3 promoter and its clinical relevance in CML. Real-time quantitative methylation-specific PCR and bisulfite sequencing PCR was performed to detect the level of GPX3 methylation in 80 CML patients and 44 controls. GPX3 promoter in CML patients was significantly methylated compared with controls (P = 0.007). GPX3 highly methylated patients showed significantly older age than GPX3 lowly methylated patients (P = 0.037). However, patients with GPX3 methylation had significantly lower white blood cells than those with low GPX3 methylation (P = 0.006). BCR-ABL transcript in GPX3 highly methylated patients was a little lower than that in GPX3 lowly methylated patients (P = 0.161). No significant differences were observed in the frequency of GPX3 methylation in the different stages of CML (P = 1.000). Significantly negative correlation was observed between GPX3 expression and GPX3 methylation (R = -0.442, P = 0.004). GPX3 mRNA level in K562 cell line was significantly increased after 5-aza-2'-deoxycytidine treatment, and GPX3 methylation level was decreased. GPX3 hypermethylation is frequent in CML and is negatively associated with its expression.

Nymoen DA, Hetland Falkenthal TE, Holth A, et al.
Expression and clinical role of chemoresponse-associated genes in ovarian serous carcinoma.
Gynecol Oncol. 2015; 139(1):30-9 [PubMed] Related Publications
OBJECTIVE: To validate our earlier observation that 11 chemoresistance-associated mRNAs are molecular markers of poor overall survival in ovarian serous carcinoma.
METHODS: Ovarian serous carcinomas (n=112) and solid metastases (n=63; total=175) were analyzed for mRNA expression of APC, BAG3, EGFR, S100A10, ITGAE, MAPK3, TAP1, BNIP3, MMP9, FASLG and GPX3 using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters and survival. Tumor heterogeneity was assessed in 20 cases with >1 specimen per patient. APC, BAG3, S100A10 and ERK1 protein expression by immunohistochemistry was analyzed in 58 specimens (38 primary carcinomas, 20 metastases).
RESULTS: BAG3 (p=0.013), TAP1 (p=0.014), BNIP3 (p<0.001) and MMP9 (p=0.036) were overexpressed in primary tumors, whereas S100A10 (p=0.027) and FASLG (p=0.006) were overexpressed in metastases. Analysis of patient-matched primary carcinomas and metastases showed overexpression of APC (p=0.022), MAPK3 (p=0.002) and BNIP3 (p=0.004) in the former. In primary carcinomas, higher APC (p=0.003) and MAPK3 (p=0.005) levels were related to less favorable chemoresponse. Higher S100A10 (p=0.029) and MAPK3 (p=0.041) levels were related to primary chemoresistance. Higher BAG3 (p=0.026) and APC (p=0.046) levels in primary carcinomas were significantly related to poor overall survival in univariate, though not in multivariate survival analysis. S100A10 protein expression was related to poor chemoresponse (p=0.002) and shorter overall (p=0.005) and progression-free (p<0.001) survival, the latter finding retained in multivariate analysis (p=0.035).
CONCLUSIONS: Our data provide evidence of heterogeneity in ovarian serous carcinoma and identify APC, MAPK3, BAG3 and S100A10 as potential biomarkers of poor chemotherapy response and/or poor outcome in this cancer.

Rudenko E, Kondratov O, Gerashchenko G, et al.
Aberrant expression of selenium-containing glutathione peroxidases in clear cell renal cell carcinomas.
Exp Oncol. 2015; 37(2):105-10 [PubMed] Related Publications
AIM: To find putative diagnostic markers for clear cell renal cell carcinomas (ccRCC).
MATERIAL AND METHODS: Quantitative polymerase chain reaction (Q-PCR), bisulfite treatment, methylation-specific PCR, analysis on cBioPortal for Cancer Genomics.
RESULTS: We have found that expression of GPX1, GPX3, and GPX4 genes was decreased in ccRCC. We have shown that the number of alanine (GCG) repeats at the amino terminus of the GPX1 protein is variable. It was reported earlier that an allele that possess 5 alanine repeats is associated with the increased cancer risk. According to the obtained data, the allele with the 5 alanine repeats was also present in a group of healthy donors. Moreover, the frequency of alleles with repeats was similar among ccRCC patients and healthy individuals. We found that decreased expression of GPXs genes was not associated with promoter methylation. To provide other explanation, an analysis on the gene copy number was performed. We have found the heterozygous deletions for GPX1 gene, amplification for GPX3 gene, and no change in gene copy number for GPX4.
CONCLUSIONS: Our data support the hypothesis that GPX1, GPX3, and GPX4 genes may play a role in ccRCC cancerogenesis and therefore they might be considered as putative diagnostic markers for ccRCC.

Liu Q, Jin J, Ying J, et al.
Frequent epigenetic suppression of tumor suppressor gene glutathione peroxidase 3 by promoter hypermethylation and its clinical implication in clear cell renal cell carcinoma.
Int J Mol Sci. 2015; 16(5):10636-49 [PubMed] Free Access to Full Article Related Publications
The goal of this study is to identify novel tumor suppressor genes silenced by promoter methylation in clear cell renal cell carcinoma (ccRCC) and discover new epigenetic biomarkers for early cancer detection. Reactive oxygen species (ROS) is a major cause of DNA damage that correlates with cancer initiation and progression. Glutathione peroxidase 3 (GPX3), the only known extracellular glycosylated enzyme of GPXs, is a major scavenger of ROS. GPX3 has been identified as a tumor suppressor in many cancers. However, the role of GPX3 in ccRCC remains unclear. This study aimed to investigate its epigenetic alteration in ccRCC and possible clinicopathological association. In our study, GPX3 methylation and down-regulation were detected in 5 out of 6 ccRCC cell lines and the GPX3 mRNA and protein expression level in ccRCC tumors was significantly lower than in adjacent non-malignant renal tissues (p<0.0001). Treatment with 5-Aza-2'-deoxycytidine restored GPX3 expression in ccRCC cells. Aberrant methylation was further detected in 77.1% (162/210) of RCC primary tumors, but only 14.6% (7/48) in adjacent non-malignant renal tissues. GPX3 methylation status was significantly associated with higher tumor nuclear grade (p=0.014). Thus, our results showing frequent GPX3 inactivation by promoter hypermethylation in ccRCC may reveal the failure in the cellular antioxidant system in ccRCC and may be associated with renal tumorigenesis. GPX3 tumor specific methylation may serve as a biomarker for early detection and prognosis prediction of ccRCC.

Zhao H, Li J, Li X, et al.
Silencing GPX3 Expression Promotes Tumor Metastasis in Human Thyroid Cancer.
Curr Protein Pept Sci. 2015; 16(4):316-21 [PubMed] Related Publications
The incidence of thyroid cancer has been increased in the past few decades. GPX3 gene is located in 5q23, which is frequently deleted in prostate cancer. Methylation of GPX3 was found frequently in prostate, esophagus, gastric and breast cancers. To detect the expression and analyze the mechanism of GPX3 in human thyroid cancer, 94 cases of primary papillary thyroid cancer (PTC) which coupled with adjacent tissue samples, as well as 15 cases of normal thyroid epithelial tissue samples were collected. Methylation specific PCR (MSP), immunohistochemistry staining, transwell assay and siRNA knockdown technique were employed. GPX3 was methylated in 46.8% (44 of 94) of PTC and methylation of GPX3 was associated with tumor size (P<0.05) and regional lymph node metastasis (P<0.01) significantly. Consistent expression of GPX3 was observed in the adjacent tissue samples and absent/reduced expression of GPX3 was found frequently in primary PTC samples. In 44 cases of methylated cancer samples, loss of/ reduced expression was found in 36 cases and expression of GPX3 was found in 8 cases. In 50 cases of unmethylated PTC samples, loss of/ reduced expression was found in 31 cases and expression of GPX3 was found in 19 cases. Lost/ reduced expression of GPX3 is associated with promoter region hypermethylation (P<0.05). Wnt signaling was inhibited by GPX3 in TPC-1 and FTC133 cells. In conclusion, GPX3 is frequently methylated in human papillary thyroid cancer and the expression of GPX3 was regulated by promoter region methylation. Methylation of GPX3 is related to tumor size and lymph node metastasis. Metastasis of thyroid cancer was suppressed by GPX3 through inhibition Wnt/β-catenin signaling.

Zhao H, Tang J, Xu J, et al.
Selenoprotein Genes Exhibit Differential Expression Patterns Between Hepatoma HepG2 and Normal Hepatocytes LO2 Cell Lines.
Biol Trace Elem Res. 2015; 167(2):236-41 [PubMed] Related Publications
The purpose of this study was to compare messenger RNA (mRNA) expression of selenoprotein genes between hepatoma HepG2 and normal hepatocytes LO2 cell lines. Liver HepG2 and LO2 cells were cultured in 12-well plates under the same condition until cells grew to complete confluence, and then cells were harvested for total RNA and protein extraction. The qPCRs were performed to compare gene expression of 14 selenoprotein genes and 5 cancer signaling-related genes. Enzyme activities were also assayed. The results showed that human hepatoma HepG2 cells grew faster than normal hepatocytes LO2 cells. Among the genes investigated, 10 selenoprotein genes (Gpx1, Gpx3, Gpx4, Selx, Sepp, Sepw1, Sepn1, Selt, Seli, Selh) and 3 cancer signaling-related genes (Bcl-2A, caspase-3, and P38) were upregulated (P < 0.05), while Selo and Bcl-2B were downregulated (P < 0.05) in hepatoma HepG2 cells compared to LO2 cells. Significant correlations were found between selenoprotein genes and the cancer signaling-related genes Caspase3, P53, Bc1-2A, and Bc1-2B. Our results revealed that selenoprotein genes were aberrantly expressed in hepatoma HepG2 cells compared to normal liver LO2 cells, which indicated that those selenoprotein genes may play important roles in the occurrence and development of liver carcinogenesis.

de Cubas AA, Korpershoek E, Inglada-Pérez L, et al.
DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers.
Clin Cancer Res. 2015; 21(13):3020-30 [PubMed] Related Publications
PURPOSE: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers.
EXPERIMENTAL DESIGN: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic).
RESULTS: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Δβmetastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity.
CONCLUSIONS: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases.

Cao S, Yan B, Lu Y, et al.
Methylation of promoter and expression silencing of GPX3 gene in hepatocellular carcinoma tissue.
Clin Res Hepatol Gastroenterol. 2015; 39(2):198-204 [PubMed] Related Publications
BACKGROUND/AIMS: Accumulating evidence has identified transcriptional silencing by aberrant methylation of CpG islands as a potential mechanism for the inactivation of tumor suppressor genes. The role of aberrant methylation of the GPX3 promoter in hepatocellular carcinoma (HCC) is not yet clear. We investigated the association of the status of GPX3 promoter methylation and GPX3 protein expression with the clinicopathological progression of HCC.
METHODOLOGY: Sixty HCC tumor and matched non-cancerous tissues were included in this study, and methylation was examined using MSP. GPX3 mRNA and protein levels were evaluated using RT-PCR and western blot analysis, respectively. Clinicopathological data were compiled for correlation analyses.
RESULTS: Among the 60 HCC cases, 76.7% (46/60) showed at elevated DNA methylation and displayed significantly lower levels of GPX3 mRNA and protein expression. Low or undetectable GPX3 protein expression was observed in 10 of 60 tumors. GPX3 promoter methylation was detected in 46 of 60 (76.7%) tumors, while no GPX3 gene promoter methylation was observed in the matched non-cancerous specimens. There was a negative correlation between promoter methylation and GPX3 mRNA levels (P<0.05). Analysis of clinicopathological data revealed that both mRNA and protein were significantly associated with portal tumor thrombosis, metastasis and differentiation. In additional, GPX3 methylation showed a relationship with portal tumor thrombosis, metastasis and differentiation.
CONCLUSIONS: Our results suggest that promoter methylation may be a mechanism for inactivation of GPX3, possibly leading to subsequent carcinogenesis and progression of HCC.

Qi X, Ng KT, Lian QZ, et al.
Clinical significance and therapeutic value of glutathione peroxidase 3 (GPx3) in hepatocellular carcinoma.
Oncotarget. 2014; 5(22):11103-20 [PubMed] Free Access to Full Article Related Publications
AIMS: We aimed to investigate the clinical significance of GPx3 in hepatocellular carcinoma (HCC) and to characterize its tumor suppressive role.
METHODS: HCC patients (113) who underwent hepatectomy were recruited to examine the clinical relevance of GPx3. The tumor suppressive role of GPx3 was studied by administration of recombinant GPx3 (rGPx3) or over-expression of GPx3 in HCC cells in vitro and in vivo. The therapeutic value of GPx3 for HCC was further investigated using human induced pluripotent stem cell derived mesenchymal stem cells (hiPSC-MSCs) as its delivery vehicle.
RESULTS: Down-regulation of GPx3 significantly correlated with advanced tumor stage (P = 0.024), venous infiltration (P = 0.043) and poor overall survival (P = 0.007) after hepatectomy. Lower plasma GPx3 in HCC patients was significantly associated with larger tumor size (P = 0.011), more tumor nodules (P = 0.032) and higher recurrence (P = 0.016). Over-expression of GPx3 or administration of rGPx3 significantly inhibited proliferation and invasiveness of HCC cells in vitro and in vivo. Tumor suppressive activity of GPx3 was mediated through Erk-NFκB-SIP1 pathway. GPx3 could be delivered by hiPSC-MSCs into the tumor and exhibited tumor suppressive activity in vivo.
CONCLUSIONS: GPx3 is a tumor suppressor gene in HCC and may possess prognostic and therapeutic value for HCC patients.

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] Free Access to Full Article 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.

Li X, Zhou F, Jiang C, et al.
Identification of a DNA methylome profile of esophageal squamous cell carcinoma and potential plasma epigenetic biomarkers for early diagnosis.
PLoS One. 2014; 9(7):e103162 [PubMed] Free Access to Full Article Related Publications
DNA methylation is a critical epigenetic mechanism involved in key cellular processes. Its deregulation has been linked to many human cancers including esophageal squamous cell carcinoma (ESCC). This study was designed to explore the whole methylation status of ESCC and to identify potential plasma biomarkers for early diagnosis. We used Infinium Methylation 450k array to analyze ESCC tissues (n = 4), paired normal surrounding tissues (n = 4) and normal mucosa from healthy individuals (n = 4), and combined these with gene expression data from the GEO database. One hundred and sixty eight genes had differentially methylated CpG sites in their promoter region and a gene expression pattern inverse to the direction of change in DNA methylation. These genes were involved in several cancer-related pathways. Three genes were validated in additional 42 ESCC tissues and paired normal surrounding tissues. The methylation frequency of EPB41L3, GPX3, and COL14A1 were higher in tumor tissues than in normal surrounding tissues (P < 0.017). The higher methylation frequency of EPB41l3 was correlated with large tumor size (P = 0.044) and advanced pT tumor stage (P = 0.001). The higher methylation frequency of GPX3 and COL14A1 were correlated with advanced pN tumor stage (P = 0.001 and P < 0.001). The methylation of EPB41L3, GPX3, and COL14A1 genes were only found in ESCC patients' plasma, but not in normal individuals upon testing 42 ESCC patients and 50 healthy individuals. Diagnostic sensitivity was increased when methylation of any of the 3 genes were counted (64.3% sensitivity and 100% specificity). These differentially methylated genes in plasma may be used as biomarkers for early diagnosis of ESCC.

Tuft Stavnes H, Nymoen DA, Hetland Falkenthal TE, et al.
APOA1 mRNA expression in ovarian serous carcinoma effusions is a marker of longer survival.
Am J Clin Pathol. 2014; 142(1):51-7 [PubMed] Related Publications
OBJECTIVES: We previously described the overexpression of APOA1 and GPX3 in ovarian/peritoneal serous carcinoma compared with breast carcinoma effusions using gene expression array analysis. The objective of the present study was to validate this finding and to analyze the association between these genes and clinicopathologic parameters, including survival, in advanced-stage ovarian serous carcinoma.
METHODS: APOA1 and GPX3 mRNA expression using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was analyzed in 121 effusions (101 ovarian, 20 breast carcinomas) and 85 solid ovarian carcinoma specimens (43 primary carcinomas, 42 metastases).
RESULTS: APOA1 and GPX3 transcript levels were significantly higher in ovarian carcinoma at all anatomic sites compared with breast carcinoma effusions (P < .001). GPX3 mRNA levels were significantly higher in primary carcinomas and solid metastases from patients who received neoadjuvant chemotherapy compared with chemo-naïve tumors (P = .016). APOA1 and GPX3 mRNA levels in the entire effusion series were unrelated to clinicopathologic parameters. However, higher APOA1 mRNA levels in primary diagnosis pre-chemotherapy effusions were significantly related to better overall survival (P = .045), a finding that retained its significance in Cox multivariate analysis (P = .016).
CONCLUSIONS: APOA1 and GPX3 mRNA levels on qRT-PCR effectively differentiate ovarian from breast carcinoma. APOA1 may be a novel prognostic marker in metastatic serous carcinoma.

Mohamed MM, Sabet S, Peng DF, et al.
Promoter hypermethylation and suppression of glutathione peroxidase 3 are associated with inflammatory breast carcinogenesis.
Oxid Med Cell Longev. 2014; 2014:787195 [PubMed] Free Access to Full Article Related Publications
Reactive oxygen species (ROS) play a crucial role in breast cancer initiation, promotion, and progression. Inhibition of antioxidant enzymes that remove ROS was found to accelerate cancer growth. Studies showed that inhibition of glutathione peroxidase-3 (GPX3) was associated with cancer progression. Although the role of GPX3 has been studied in different cancer types, its role in breast cancer and its epigenetic regulation have not yet been investigated. The aim of the present study was to investigate GPX3 expression and epigenetic regulation in carcinoma tissues of breast cancer patients' in comparison to normal breast tissues. Furthermore, we compared GPX3 level of expression and methylation status in aggressive phenotype inflammatory breast cancer (IBC) versus non-IBC invasive ductal carcinoma (IDC). We found that GPX3 mRNA and protein expression levels were downregulated in the carcinoma tissues of IBC compared to non-IBC. However, we did not detect significant correlation between GPX3 and patients' clinical-pathological prosperities. Promoter hypermethylation of GPX3 gene was detected in carcinoma tissues not normal breast tissues. In addition, IBC carcinoma tissues showed a significant increase in the promoter hypermethylation of GPX3 gene compared to non-IBC. Our results propose that downregulation of GPX3 in IBC may play a role in the disease progression.

Zhang X, Zheng Z, Yingji S, et al.
Downregulation of glutathione peroxidase 3 is associated with lymph node metastasis and prognosis in cervical cancer.
Oncol Rep. 2014; 31(6):2587-92 [PubMed] Related Publications
Glutathione peroxidase 3 (GPX3) is a member of the glutathione peroxidase family of selenoproteins and is one of the key defensive enzymes against oxidative damages to host cells. Downregulation of GPX3 due to its promoter hypermethylation has been documented in several different types of cancer, indicating that GPX3 functions as a possible tumor suppressor. In the present study, we showed that GPX3 is also significantly downregulated in cervical cancer tissues compared to normal cervical tissues by qRT-PCR analyses and immunohistostainings. GPX3 expression was significantly related to lymph node metastasis and prognosis in cervical cancer patients. Treatment of cervical cancer cells with 5-aza-2'-deoxycytidine restored the expression of GPX3 and methylation-specific PCR (MSP) confirmed the CpG methylation of the GPX3 gene. Our results indicate that promoter methylation is one of the major causes of GPX3 downregulation in cervical cancer and GPX3 could serve as a predictive biomarker for lymph node metastasis and prognosis of cervical cancer.

Maldonado L, Brait M, Loyo M, et al.
GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer.
J Urol. 2014; 192(5):1542-8 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Recurrent prostate cancer remains a major problem. Staging, grading and prostate specific antigen level at surgery are helpful but still imperfect predictors of recurrence. For this reason there is an imperative need for additional biomarkers that add to the prediction of currently used prognostic factors.
MATERIALS AND METHODS: We evaluated the extent of promoter methylation of genes previously reported as aberrantly methylated in prostate cancer (AIM1, APC, CCND2, GPX3, GSTP1, MCAM, RARβ2, SSBP2 and TIMP3) by quantitative fluorogenic methylation-specific polymerase chain reaction. We used cancer tissue from a nested case-control study of 452 patients surgically treated for prostate cancer. Recurrence cases and controls were compared and the association between methylation extent and recurrence risk was estimated by logistic regression adjusting for patient age at prostatectomy, prostatectomy year, stage, grade, surgical margins and preprostatectomy prostate specific antigen. All statistical tests were 2-sided with p ≤0.05 considered statistically significant.
RESULTS: The extent of GSTP1 methylation was higher in patients with recurrence than in controls (p = 0.01), especially patients with early disease, ie organ confined or limited extraprostatic extension (p = 0.001). After multivariate adjustment GSTP1 promoter methylation at or above the median was associated with an increased risk of recurrence, including in men with early disease (each p = 0.05).
CONCLUSIONS: Greater GSTP1 promoter methylation in cancer tissue was independently associated with the risk of recurrence in patients with early prostate cancer. This suggests that GSTP1 promoter methylation may be a potential tissue based recurrence marker.

Farimani Sanoee M, Alizamir T, Faramarzi S, et al.
Effect of myomectomy on endometrial glutathione peroxidase 3 (GPx3) and glycodelin mRNA expression at the time of the implantation window.
Iran Biomed J. 2014; 18(2):60-6 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In fertile women, glycodelin and glutathione peroxidase 3 (GPx3) genes expression rises during the luteal phase, with a peak occurring during the implantation window. The expression of these genes decreases in women with myomas. To determine whether myomectomy would reverse glycodelin and GPx3 expression, we evaluated the transcript levels of these genes in the endometrium of patients before and after myomectomy.
METHODS: Expression of glycodelin and GPx3 genes were examined prospectively during the midluteal phase in the endometrium obtained from infertile women with myoma (n = 12) before and three months after myomectomy. Endometrial expression of these genes was evaluated using quantitative real-time RT-PCR.
RESULTS: Endometrial glycodelin mRNA expression levels (normalized to 18S rRNA expression) were increased significantly in endometrium of patients after myomectomy (P = 0.02). GPx3 mRNA expression was increased insignificantly after myomectomy (P = 0.43).
CONCLUSION: The results showed that myomectomy increased endometrial glycodelin (significantly) and GPx3 (not significantly) gene expression after 3 months. Study at different times and detecting expression of these genes can reveal more details.

Huang X, Hao C, Shen X, et al.
RUNX2, GPX3 and PTX3 gene expression profiling in cumulus cells are reflective oocyte/embryo competence and potentially reliable predictors of embryo developmental competence in PCOS patients.
Reprod Biol Endocrinol. 2013; 11:109 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. The developmental competence of oocytes and embryos in PCOS patients is reduced to a certain extent (comparing to non-PCOS patients, the high quality embryo rate was decreased by 16% from the data of our centre) during the in vitro fertilization (IVF) process. Cross-talk between the oocyte and cumulus cells is critical for oocyte maturation and embryo competence. In this study, we have evaluated the transcription of specific genes in cumulus cells harvested from pre-ovulatory follicles of PCOS patients before IVF, according to individual oocyte nuclear maturity and developmental competence. Seven genes (RUNX2, PSAT1, ADAMTS9, CXCL1, CXCL2, CXCL3, and ITGB5) were targeted from our previous cDNA microarray data which isolated genes related to oocyte nuclear maturation in PCOS patients. Two additional genes which had been found to be associated with oocyte maturation or embryo quality in non-PCOS patients (GPX3 and PTX3) were also studied.
METHODS: The mRNA expression levels of cumulus cells were detected by qRT- PCR.
RESULTS: Consistent with our previous cDNA microarray data, with the exception of GPX3 and PTX3, the selected 7 genes were related to oocyte nuclear maturation in PCOS patients. Noticeably, the expression level of RUNX2 was lower in cumulus cells derived from oocytes that could develop into blastocysts than the level of expression from oocytes that could not. The PTX3 expression level was significantly lower in cumulus cells from oocytes with two normal pronuclei than that from oocytes that formed >2 pronuclei (MPN) after fertilization. GPX3 mRNA levels were decreased in cumulus cells isolated from oocytes that developed into blastocysts with high potential development competence.
CONCLUSIONS: Several cumulus cell genes were associated with oocyte maturation, fertilization and embryo quality in PCOS patients. RUNX2 and GPX3 are candidate genetic markers in the monitoring of embryo quality for PCOS patients, whereas PTX3 mainly played a role in fertilization process. Together with morphological evaluation, cumulus cells genes may serve as biomarkers of oocyte and embryo selection during the IVF process for PCOS patients and may advance our understanding of PCOS.

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] Free Access to Full Article 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.

Lau A, Kollara A, St John E, et al.
Altered expression of inflammation-associated genes in oviductal cells following follicular fluid exposure: implications for ovarian carcinogenesis.
Exp Biol Med (Maywood). 2014; 239(1):24-32 [PubMed] Related Publications
Evidence indicates that high-grade serous ovarian carcinoma (HGSOC) may originate from lesions within the distal fallopian tube epithelium (FTE). Our previous studies indicate that fallopian tube epithelial cells from carriers of germline mutations in breast cancer susceptibility genes exhibit a pro-inflammatory gene expression signature during the luteal phase, suggesting that delayed resolution of postovulatory inflammatory signaling may contribute to predisposition to this ovarian cancer histotype. To determine whether exposure of tubal epithelial cells to periovulatory follicular fluid alters expression of inflammation-associated genes, we used an ex vivo culture system of bovine oviductal epithelial cells. Oviductal cells grown on collagen IV-coated transwell membranes assumed a cobblestone appearance and immunocytochemistry for FoxJ1 and Pax8 indicated that both ciliated and secretory epithelial cells were maintained in the cultures. Oviductal cells were exposed to human follicular fluid or culture medium for 24 h following which total cellular RNA was extracted at various time points. Expression of genes associated with inflammation was determined by quantitative real-time RT-PCR. Exposure to follicular fluid transiently increased the transcript levels of interleukin 8 (IL8) and cyclooxygenase 2 (PTGS2), and decreased the expression of mitochondrial superoxide dismutase (SOD2), glutathione peroxidase 3 (GPX3), disabled homolog 2 (DAB2), and glucocorticoid receptor (NR3C1). Tumor necrosis factor (TNF) and IL6 levels were also decreased while those of nicotinomide phosphoribosyltransferase (NAMPT) were unaffected. This study demonstrates that periovulatory follicular fluid can act directly upon oviductal epithelial cells to alter gene expression that might contribute to early carcinogenic events. Furthermore, these findings illustrate the potential use of bovine oviductal cells to study signaling events implicated in ovarian carcinogenesis.

Yang ZL, Yang L, Zou Q, et al.
Positive ALDH1A3 and negative GPX3 expressions are biomarkers for poor prognosis of gallbladder cancer.
Dis Markers. 2013; 35(3):163-72 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Gallbladder cancers (GBCs) are highly aggressive cancers with high mortality. However, biological markers for the progression and prognosis of GBC are currently unavailable in the clinic.
OBJECTIVE: To identify biomarkers for predicting GBC metastasis and prognosis.
METHODS: We examined ALDH1A3 and GPX3 expressions in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) by using immunohistochemistry.
RESULTS: Positive ALDH1A3 and negative GPX3 expressions were significantly associated with lymph node metastasis and invasion of SC/ASCs and ACs. Univariate Kaplan-Meier analysis showed that either positive ALDH1A3 (P < 0.001) or negative GPX3 (P < 0.001) expression significantly correlated with decreased overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive ALDH1A3 expression or negative GPX3 expression was an independent poor-prognostic predictor in both SC/ASC and AC patients.
CONCLUSIONS: Our study suggested that positive ALDH1A3 and negative GPX3 expressions are closely associated with clinical pathological behaviors and poor prognosis of gallbladder cancer.

de Melo CF, Gigek CO, da Silva JN, et al.
Association of COX2 gene hypomethylation with intestinal type gastric cancer in samples of patients from northern Brazil.
Tumour Biol. 2014; 35(2):1107-11 [PubMed] Related Publications
To verify the methylation status of THBS1, GPX3, and COX2 genes and to evaluate their association with Helicobacter pylori in gastric adenocarcinomas. Methylation-sensitive restriction enzyme PCR assay was performed in 16 diffuse type gastric cancer samples, 23 intestinal type, and 15 normal stomach tissue. The presence of H. pylori was performed by amplification of the fragment of the 16S rRNA. Statistical analyses were performed using Fisher's exact test. The hypermethylation of GPX3, THBS1, and COX2 occurred in 18 (n = 7), 5 (n = 2), and 36 % (n = 14) of gastric cancer samples, respectively, whereas in normal samples, it was found in 13, 7, and 67 %. The presence of H. pylori was detected in 67 % of gastric cancer samples and 67 % in normal gastric samples. The methylation of THBS1 and GPX3 was not significantly different between the types of tumors, normal sample, the presence of H. pylori, or clinicopathological variables studied (P > 0.05). However, the methylation status of the gene COX2 is significantly different between normal tissue and intestinal type gastric cancer (P = 0.02). Therefore, our results suggest that the methylation status of the gene COX2 is associated with the intestinal type of gastric cancer.

Kraus S, Hummler S, Toriola AT, et al.
Impact of genetic polymorphisms on adenoma recurrence and toxicity in a COX2 inhibitor (celecoxib) trial: results from a pilot study.
Pharmacogenet Genomics. 2013; 23(8):428-37 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities.
METHODS: Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2≥0.90, MAF≥4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology.
RESULTS: Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66-26.36, P<0.01) to 10.71 (95% confidence interval 1.96-58.60, P<0.01).
CONCLUSION: Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.

Kaiser MF, Johnson DC, Wu P, et al.
Global methylation analysis identifies prognostically important epigenetically inactivated tumor suppressor genes in multiple myeloma.
Blood. 2013; 122(2):219-26 [PubMed] Free Access to Full Article Related Publications
Outcome in multiple myeloma is highly variable and a better understanding of the factors that influence disease biology is essential to understand and predict behavior in individual patients. In the present study, we analyzed combined genomewide DNA methylation and gene expression data of patients treated in the Medical Research Council Myeloma IX trial. We used these data to identify epigenetically repressed tumor suppressor genes with prognostic relevance in myeloma. We identified 195 genes with changes in methylation status that were significantly associated with prognosis. Combining DNA methylation and gene expression data led to the identification of the epigenetically regulated tumor modulating genes GPX3, RBP1, SPARC, and TGFBI. Hypermethylation of these genes was associated with significantly shorter overall survival, independent of age, International Staging System score, and adverse cytogenetics. The 4 differentially methylated and expressed genes are known to mediate important tumor suppressive functions including response to chemotherapy (TGFBI), interaction with the microenvironment (SPARC), retinoic acid signaling (RBP1), and the response to oxidative stress (GPX3), which could explain the prognostic impact of their differential methylation. Assessment of the DNA methylation status of the identified genes could contribute to the molecular characterization of myeloma, which is prerequisite for an individualized treatment approach.

Qu Y, Dang S, Hou P
Gene methylation in gastric cancer.
Clin Chim Acta. 2013; 424:53-65 [PubMed] Related Publications
Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field.

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