Showing papers on "GPX3 published in 2023"

Glutathione-Related Enzymes and Proteins: A Review

Abstract: The tripeptide glutathione is found in all eukaryotic cells, and due to the compartmentalization of biochemical processes, its synthesis takes place exclusively in the cytosol. At the same time, its functions depend on its transport to/from organelles and interorgan transport, in which the liver plays a central role. Glutathione is determined as a marker of the redox state in many diseases, aging processes, and cell death resulting from its properties and reactivity. It also uses other enzymes and proteins, which enables it to engage and regulate various cell functions. This paper approximates the role of these systems in redox and detoxification reactions such as conjugation reactions of glutathione-S-transferases, glyoxylases, reduction of peroxides through thiol peroxidases (glutathione peroxidases, peroxiredoxins) and thiol–disulfide exchange reactions catalyzed by glutaredoxins.

Side-by-side comparison of recombinant human glutathione peroxidases identifies overlapping substrate specificities for soluble hydroperoxides

Abstract: Five out of eight human glutathione peroxidases (GPXs) are selenoproteins, representing proteins that contain selenium as part of the amino acid selenocysteine. The GPXs are important for reducing hydroperoxides in a glutathione-consuming manner and thus regulate cellular redox homeostasis. GPX1, GPX2, and GPX4 represent the three main cytosolic GPXs, but they differ in their expression patterns with GPX1 and GPX4 being expressed ubiquitously, whereas GPX2 is mainly expressed in epithelial cells. GPX1 and GPX2 have been described to reduce soluble hydroperoxides, while GPX4 reduces complex lipid hydroperoxides, thus protecting cells from lipid peroxidation and ferroptosis. But most of these data are derived from cells that are devoid of one of the isoforms and thus, compensation or other cellular effects might affect the conclusions. So far, the use of isolated recombinant human selenoprotein glutathione peroxidases in pure enzyme assays has not been employed to study their substrate specificities side by side. Using recombinant GPX1, GPX2, and GPX4 produced in E. coli we here assessed their GPX activities by a NADPH-consuming glutathione reductase-coupled assay with 17 different peroxides (all at 50 μM) as substrates. GPX4 was clearly the only isoform able to reduce phosphatidylcholine hydroperoxide. In contrast, small soluble hydroperoxides such as H2O2, cumene hydroperoxide, and tert-butyl hydroperoxide were reduced by all three isoforms, but with approximately 10-fold higher efficiency for GPX1 in comparison to GPX2 and GPX4. Also, several fatty acid-derived hydroperoxides were reduced by all three isoforms and again GPX1 had the highest activity. Interestingly, the stereoisomerism of the fatty acid-derived hydroperoxides clearly affected the activity of the GPX enzymes. Overall, distinct substrate specificity is obvious for GPX4, but not so when comparing GPX1 and GPX2. Clearly GPX1 was the most potent isoform of the three GPXs in terms of turnover in reduction of soluble and fatty-acid derived hydroperoxides.

Supplementary Figure 3 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 2275K, Gpx3 expression is downregulated in human colon cancer samples. A) GPX3 expression is significantly downregulated in adenomas and colorectal cancer patients compared with normal adjacent colon tissues. **P<0.01 for each stage relative to normal. B) GPX3 expression in matched human normal and tumor samples. Error bars represent standard deviation of samples performed in duplicate. C) Western blot of GPX3 protein expression in matched human normal and tumor samples. Quantification is presented as fold change intensity controlled for -actin.</p>

Supplementary Figure 6 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - Gpx3 expression is highest in Caco2 cells. A) Gpx3 expression was analyzed within a cohort of colorectal cancer cell lines. The graph demonstrates fold-change of triplicate samples after analysis by the delta deltaCt method. B) Western blot for Gpx3 expression in Caco2 and HCT116 cells.</p>

Decreased GPX3 mRNA level in peripheral blood mononuclear cells is associated with HBV-related hepatocellular carcinoma.

Abstract: BACKGROUND Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common malignancies with increasing mortality. In this study, we aim to determine the alteration and diagnostic value of GXP3 expression for HBV-related HCC. METHODS We recruited 243 subjects, including 132 HBV-related HCC patients, 78 chronic hepatitis B (CHB) patients and 33 healthy controls (HCs). The mRNA level of GPX3 in peripheral blood mononuclear cells (PBMCs) was assessed by quantitative real-time PCR. The GPX3 plasma level was detected by ELISA. RESULTS The GPX3 mRNA level was significantly decreased in HBV-related HCC patients compared with in CHB patients and HCs (p<0.05). The plasma GPX3 level was significantly lower in patients with HBV-related HCC than in CHB patients and HCs (p<0.05). In the HCC subgroup, the GPX3 mRNA level was significantly lower in patients with positive HBeAg, ascites, advanced stage and poor differentiation compared with in the other groups (p<0.05). The receiver operating characteristic curve was constructed to estimate the diagnostic value of the GPX3 mRNA level for HBV-related HCC. The GPX3 mRNA level showed a significantly better diagnostic ability compared with alpha fetoprotein (AFP) (area under the curve 0.769 vs 0.658, p<0.001). CONCLUSIONS A decreased GPX3 mRNA level might be a potential non-invasive biomarker for HBV-related HCC. It showed better diagnostic ability than AFP.

Data from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <div>Abstract<p>The glutathione peroxidases, a family of selenocysteine-containing redox enzymes, play pivotal roles in balancing the signaling, immunomodulatory, and deleterious effects of reactive oxygen species (ROS). The glutathione peroxidase GPX3 is the only extracellular member of this family, suggesting it may defend cells against ROS in the extracellular environment. Notably, GPX3 hypermethylation and underexpression occur commonly in prostate, gastric, cervical, thyroid, and colon cancers. We took a reverse genetics approach to investigate whether GPX3 would augment inflammatory colonic tumorigenesis, a process characterized by oxidative stress and inflammation, comparing <i>Gpx3</i>^−/− mice in an established two-stage model of inflammatory colon carcinogenesis. <i>Gpx3</i>-deficient mice exhibited an increased tumor number, though not size, along with a higher degree of dysplasia. In addition, they exhibited increased inflammation with redistribution toward protumorigenic M2 macrophage subsets, increased proliferation, hyperactive WNT signaling, and increased DNA damage. To determine the impact of acute gene loss in an established colon cancer line, we silenced <i>GPX3</i> in human Caco2 cells, resulting in increased ROS production, DNA damage and apoptosis in response to oxidative stress, combined with decreased contact-independent growth. Taken together, our results suggested an immunomodulatory role for GPX3 that limits the development of colitis-associated carcinoma. <i>Cancer Res; 73(3); 1245–55. ©2012 AACR</i>.</p></div>

Data from Glutathione Peroxidase 3, Deleted or Methylated in Prostate Cancer, Suppresses Prostate Cancer Growth and Metastasis

Abstract: <div>Abstract<p>Glutathione peroxidase 3 is a selenium-dependent enzyme playing a critical role in detoxifying reactive oxidative species and maintaining the genetic integrity of mammalian cells. In this report, we found that the expression of glutathione peroxidase 3 (<i>GPx3</i>) was widely inactivated in prostate cancers. Complete inactivation of <i>GPx3</i> correlates with a poor clinical outcome. Deletions (hemizygous and homozygous) of GPx3 gene are frequent in prostate cancer samples, occurring in 39% of the samples studied. The rate of methylation of the GPx3 exon 1 region in prostate cancer samples reaches 90%. Overexpression of <i>GPx3</i> in prostate cancer cell lines induced the suppression of colony formation and anchorage-independent growth of PC3, LNCaP, and Du145 cells. PC3 cells overexpressing <i>GPx3</i> reduced invasiveness in Matrigel transmigration analysis by an average of 2.7-fold. Xenografted PC3 cells expressing GPx3 showed reduction in tumor volume by 4.8-fold, elimination of metastasis (0/16 versus 7/16), and reduction of animal death (3/16 versus 16/16). The tumor suppressor activity of <i>GPx3</i> seems to relate to its ability to suppress the expression of <i>c-met</i>. The present findings suggest that <i>GPx3</i> is a novel tumor suppressor gene. [Cancer Res 2007;67(17):8043–50]</p></div>

Data from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <div>Abstract<p>The glutathione peroxidases, a family of selenocysteine-containing redox enzymes, play pivotal roles in balancing the signaling, immunomodulatory, and deleterious effects of reactive oxygen species (ROS). The glutathione peroxidase GPX3 is the only extracellular member of this family, suggesting it may defend cells against ROS in the extracellular environment. Notably, GPX3 hypermethylation and underexpression occur commonly in prostate, gastric, cervical, thyroid, and colon cancers. We took a reverse genetics approach to investigate whether GPX3 would augment inflammatory colonic tumorigenesis, a process characterized by oxidative stress and inflammation, comparing <i>Gpx3</i>^−/− mice in an established two-stage model of inflammatory colon carcinogenesis. <i>Gpx3</i>-deficient mice exhibited an increased tumor number, though not size, along with a higher degree of dysplasia. In addition, they exhibited increased inflammation with redistribution toward protumorigenic M2 macrophage subsets, increased proliferation, hyperactive WNT signaling, and increased DNA damage. To determine the impact of acute gene loss in an established colon cancer line, we silenced <i>GPX3</i> in human Caco2 cells, resulting in increased ROS production, DNA damage and apoptosis in response to oxidative stress, combined with decreased contact-independent growth. Taken together, our results suggested an immunomodulatory role for GPX3 that limits the development of colitis-associated carcinoma. <i>Cancer Res; 73(3); 1245–55. ©2012 AACR</i>.</p></div>

Supplementary Figure 1 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 2063K, Gpx3 is decreased in plasma of mice subjected to the AOM/DSS protocol. Western blot of Gpx3 protein expression in plasma from WT water treated and AOM/DSS treated mice (top). Quantification is presented as fold change intensity and the graph (bottom) displays plasma Gpx3 protein in the mice shown in the western blot above. P=0.046.</p>

Supplementary Figure Legend from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 122K</p>

Supplementary Figure 4 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 2173K, Absence of Gpx3 does not modify weight change in response to AOM/DSS exposure. Percentage weight loss at day 0 and day 7 of each cycle throughout the course of the AOM/DSS protocol. P=n.s.</p>

Supplementary Figure 6 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - Gpx3 expression is highest in Caco2 cells. A) Gpx3 expression was analyzed within a cohort of colorectal cancer cell lines. The graph demonstrates fold-change of triplicate samples after analysis by the delta deltaCt method. B) Western blot for Gpx3 expression in Caco2 and HCT116 cells.</p>

The Discovery of Glutathione Peroxidases: Milestones in Understanding the Biological Role of Selenium und Sulfur

Abstract: With the discovery of glutathione peroxidase (GPx1), the role of glutathione in counteracting oxidative challenge became clear. GPx1 was the first selenoprotein discovered in mammals. It contains a selenocysteine residue integrated into the peptide chain. The phospholipid hydroperoxide glutathione peroxidase (GPx4) also proved to be a selenoprotein. In the cytosol, it inhibits lipid peroxidation and ferroptosis; in the nucleus, it supports protamine compaction; its mitochondrial expression form builds the sheath surrounding the mitochondria in spermatozoa and is essential for male fertility. In the meantime, glutathione peroxidases have grown into a large family of enzymes that work with selenium or with sulfur catalysis. With the growing knowledge that hydroperoxides are not just toxic, but normal intermediates of biosynthetic processes and signaling molecules, glutathione peroxidases had to be re-considered as regulatory proteins in signaling cascades, as modulators of enzyme activities, or as hydrogen peroxide sensors. The extraordinary catalytic efficiency of both the selenium- and sulfur-containing enzymes remained enigmatic for a long time. Recent quantum mechanical approaches revealed a concerted dual attack on the peroxide bond, which explains why their speed of peroxide reduction is orders of magnitude higher than that of any low molecular weight thiol or selenol.

Supplementary Figure 4 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 2173K, Absence of Gpx3 does not modify weight change in response to AOM/DSS exposure. Percentage weight loss at day 0 and day 7 of each cycle throughout the course of the AOM/DSS protocol. P=n.s.</p>

Supplementary Figure 5 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 1856K, Intratumoral apoptosis is not altered in Gpx3-/- mice. TUNEL immunohistochemistry was performed to identify apoptotic cells in WT (N=13) and Gpx3-/- (N=14) tumors. TUNEL+ cells were counted within each high-powered field (HPF) and then averaged for each mouse. P=n.s.</p>

Increased expression of glutathione peroxidase 3 prevents tendinopathy by suppressing oxidative stress

Abstract: Tendinopathy, a degenerative disease, is characterized by pain, loss of tendon strength, or rupture. Previous studies have identified multiple risk factors for tendinopathy, including aging and fluoroquinolone use; however, its therapeutic target remains unclear. We analyzed self-reported adverse events and the US commercial claims data and found that the short-term use of dexamethasone prevented both fluoroquinolone-induced and age-related tendinopathy. Rat tendons treated systemically with fluoroquinolone exhibited mechanical fragility, histological change, and DNA damage; co-treatment with dexamethasone attenuated these effects and increased the expression of the antioxidant enzyme glutathione peroxidase 3 (GPX3), as revealed via RNA-sequencing. The primary role of GPX3 was validated in primary cultured rat tenocytes treated with fluoroquinolone or H2O2, which accelerates senescence, in combination with dexamethasone or viral overexpression of GPX3. These results suggest that dexamethasone prevents tendinopathy by suppressing oxidative stress through the upregulation of GPX3. This steroid-free approach for upregulation or activation of GPX3 can serve as a novel therapeutic strategy for tendinopathy.

Antioxidant Genetic Variants Modify Echocardiography Indices in Long COVID

Abstract: Although disturbance of redox homeostasis might be responsible for COVID-19 cardiac complications, this molecular mechanism has not been addressed yet. We have proposed modifying the effects of antioxidant proteins polymorphisms (superoxide dismutase 2 (SOD2), glutathione peroxidase 1 (GPX1), glutathione peroxidase 3 (GPX3) and nuclear factor erythroid 2-related factor 2, (Nrf2)) in individual susceptibility towards the development of cardiac manifestations of long COVID-19. The presence of subclinical cardiac dysfunction was assessed via echocardiography and cardiac magnetic resonance imaging in 174 convalescent COVID-19 patients. SOD2, GPX1, GPX3 and Nrf2 polymorphisms were determined via the appropriate PCR methods. No significant association of the investigated polymorphisms with the risk of arrhythmia development was found. However, the carriers of variant GPX1*T, GPX3*C or Nrf2*A alleles were more than twice less prone for dyspnea development in comparison with the carriers of the referent ones. These findings were even more potentiated in the carriers of any two variant alleles of these genes (OR = 0.273, and p = 0.016). The variant GPX alleles were significantly associated with left atrial and right ventricular echocardiographic parameters, specifically LAVI, RFAC and RV-EF (p = 0.025, p = 0.009, and p = 0.007, respectively). Based on the relation between the variant SOD2*T allele and higher levels of LV echocardiographic parameters, EDD, LVMI and GLS, as well as troponin T (p = 0.038), it can be proposed that recovered COVID-19 patients, who are the carriers of this genetic variant, might have subtle left ventricular systolic dysfunction. No significant association between the investigated polymorphisms and cardiac disfunction was observed when cardiac magnetic resonance imaging was performed. Our results on the association between antioxidant genetic variants and long COVID cardiological manifestations highlight the involvement of genetic propensity in both acute and long COVID clinical manifestations.

Supplementary Figure 3 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 2275K, Gpx3 expression is downregulated in human colon cancer samples. A) GPX3 expression is significantly downregulated in adenomas and colorectal cancer patients compared with normal adjacent colon tissues. **P<0.01 for each stage relative to normal. B) GPX3 expression in matched human normal and tumor samples. Error bars represent standard deviation of samples performed in duplicate. C) Western blot of GPX3 protein expression in matched human normal and tumor samples. Quantification is presented as fold change intensity controlled for -actin.</p>

Supplementary Figure 2 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 1974K, Gpx3 expression is not increased in tumor compared to normal tissue. Normal and tumor tissue mRNA expression of Gpx3 in WT normal adjacent and WT tumor tissue post-AOM/DSS. Error bars represent standard error of four mice performed in triplicate. P=n.s.</p>

Supplementary Figure 5 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 1856K, Intratumoral apoptosis is not altered in Gpx3-/- mice. TUNEL immunohistochemistry was performed to identify apoptotic cells in WT (N=13) and Gpx3-/- (N=14) tumors. TUNEL+ cells were counted within each high-powered field (HPF) and then averaged for each mouse. P=n.s.</p>

Development of an assay pipeline for the discovery of novel small molecule inhibitors of human glutathione peroxidases GPX1 and GPX4

Abstract: Selenoprotein glutathione peroxidases (GPX), like ubiquitously expressed GPX1 and the ferroptosis modulator GPX4, enact antioxidant activities by reducing hydroperoxides using glutathione. Overexpression of these enzymes is common in cancer and can be associated with the development of resistance to chemotherapy. GPX1 and GPX4 inhibitors have thus shown promise as anti-cancer agents, and targeting other GPX isoforms may prove equally beneficial. Existing inhibitors are often promiscuous, or modulate GPXs only indirectly, so novel direct inhibitors identified through screening against GPX1 and GPX4 could be valuable. Here, we developed optimized glutathione reductase (GR)-coupled GPX assays for the biochemical high-throughput screen (HTS) of almost 12,000 compounds with proposed mechanisms of action. Initial hits were triaged using a GR counter-screen, assessed for isoform specificity against an additional GPX isoform, GPX2, and were assessed for general selenocysteine-targeting activity using a thioredoxin reductase (TXNRD1) assay. Importantly, 70% of the GPX1 inhibitors identified in the primary screen, including several cephalosporin antibiotics, were found to also inhibit TXNRD1, while auranofin, previously known as a TXNRD1 inhibitor, also inhibited GPX1 (but not GPX4). Additionally, every GPX1 inhibitor identified (including omapatrilat, tenatoprazole, cefoxitin and ceftibuten) showed similar inhibitory activity against GPX2. Some compounds inhibiting GPX4 but not GPX1 or GPX2, also inhibited TXNRD1 (26%). Compounds only inhibiting GPX4 included pranlukast sodium hydrate, lusutrombopag, brilanestrant, simeprevir, grazoprevir (MK-5172), paritaprevir, navitoclax, venetoclax and VU0661013. Two compounds (metamizole sodium and isoniazid sodium methanesulfate) inhibited all three GPXs but not TXNRD1, while 2,3-dimercaptopropanesulfonate, PI4KIII beta inhibitor 3, SCE-2174 and cefotetan sodium inhibited all tested selenoproteins (but not GR). The detected overlaps in chemical space suggest that the counter screens introduced here should be imperative for identification of specific GPX inhibitors. With this approach, we could indeed identify novel GPX1/GPX2- or GPX4-specific inhibitors, thus presenting a validated pipeline for future identification of specific selenoprotein-targeting agents. Our study also identified GPX1/GPX2, GPX4 and/or TXNRD1 as targets for several previously developed pharmacologically active compounds.

Supplementary Figure 2 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 1974K, Gpx3 expression is not increased in tumor compared to normal tissue. Normal and tumor tissue mRNA expression of Gpx3 in WT normal adjacent and WT tumor tissue post-AOM/DSS. Error bars represent standard error of four mice performed in triplicate. P=n.s.</p>

Supplementary Figure 1 from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 2063K, Gpx3 is decreased in plasma of mice subjected to the AOM/DSS protocol. Western blot of Gpx3 protein expression in plasma from WT water treated and AOM/DSS treated mice (top). Quantification is presented as fold change intensity and the graph (bottom) displays plasma Gpx3 protein in the mice shown in the western blot above. P=0.046.</p>

Data from Glutathione Peroxidase 3, Deleted or Methylated in Prostate Cancer, Suppresses Prostate Cancer Growth and Metastasis

Abstract: <div>Abstract<p>Glutathione peroxidase 3 is a selenium-dependent enzyme playing a critical role in detoxifying reactive oxidative species and maintaining the genetic integrity of mammalian cells. In this report, we found that the expression of glutathione peroxidase 3 (<i>GPx3</i>) was widely inactivated in prostate cancers. Complete inactivation of <i>GPx3</i> correlates with a poor clinical outcome. Deletions (hemizygous and homozygous) of GPx3 gene are frequent in prostate cancer samples, occurring in 39% of the samples studied. The rate of methylation of the GPx3 exon 1 region in prostate cancer samples reaches 90%. Overexpression of <i>GPx3</i> in prostate cancer cell lines induced the suppression of colony formation and anchorage-independent growth of PC3, LNCaP, and Du145 cells. PC3 cells overexpressing <i>GPx3</i> reduced invasiveness in Matrigel transmigration analysis by an average of 2.7-fold. Xenografted PC3 cells expressing GPx3 showed reduction in tumor volume by 4.8-fold, elimination of metastasis (0/16 versus 7/16), and reduction of animal death (3/16 versus 16/16). The tumor suppressor activity of <i>GPx3</i> seems to relate to its ability to suppress the expression of <i>c-met</i>. The present findings suggest that <i>GPx3</i> is a novel tumor suppressor gene. [Cancer Res 2007;67(17):8043–50]</p></div>

The Role of Glutathione in Selected Viral Diseases

Abstract: During inflammatory processes, immunocompetent cells are exposed to substantial amounts of free radicals and toxic compounds. Glutathione is a cysteine-containing tripeptide that is an important and ubiquitous antioxidant molecule produced in human organs. The intracellular content of GSH regulates the detoxifying capacity of cells, as well as the inflammatory and immune response. GSH is particularly important in the liver, where it serves as the major non-protein thiol involved in cellular antioxidant defense. There are numerous causes of hepatitis. The inflammation of the liver can be caused by a variety of infectious viruses. The relationship between oxidative stress and the hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis E virus (HEV) infection is not fully known. The aim of this study was to examine the relationship between hepatotropic viruses and glutathione status, including reduced glutathione (GSH) and oxidized glutathione (GSSG), as well as antioxidant enzymes, e.g., glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) in liver diseases.

GPX3 expression was down-regulated but positively correlated with poor outcome in human cancers

Abstract: Introduction Cancer is a crucial public health problem and one of the leading causes of death worldwide. Previous studies have suggested that GPX3 may be involved in cancer metastasis and chemotherapy resistance. However, how GPX3 affects cancer patients’ outcomes and the underlying mechanism remains unclear. Methods Sequencing data and clinical data from TCGA, GTEx, HPA, and CPTAC were used to explore the relationship between GPX3 expression and clinical features. Immunoinfiltration scores were used to assess the relationship between GPX3 and the tumor immune microenvironment. Functional enrichment analysis was used to predict the role of GPX3 in tumors. Gene mutation frequency, methylation level, and histone modification were used to predict the GPX3 expression regulation method. Breast, ovarian, colon, and gastric cancer cells were used to investigate the relationship between GPX3 expression and cancer cell metastasis, proliferation, and chemotherapy sensitivity. Results GPX3 is down-regulated in various tumor tissues, and GPX3 expression level can be used as a marker for cancer diagnosis. However, GPX3 expression is associated with higher stage and lymph node metastasis, as well as poorer prognosis. GPX3 is closely related to thyroid function and antioxidant function, and its expression may be regulated by epigenetic inheritance such as methylation modification or histone modification. In vitro experiments, GPX3 expression is associated with cancer cell sensitivity to oxidant and platinum-based chemotherapy and is involved in tumor metastasis in oxidative environments. Discussion We explored the relationship between GPX3 and clinical features, immune infiltration characteristics, migration and metastasis, and chemotherapy sensitivities of human cancers. We further investigated the potential genetic and epigenetic regulation of GPX3 in cancer. Our results suggested that GPX3 plays a complicated role in the tumor microenvironment, simultaneously promoting metastasis and chemotherapy resistance in human cancers.

Supplementary Figure Legend from Tumor Suppressor Function of the Plasma Glutathione Peroxidase Gpx3 in Colitis-Associated Carcinoma

Abstract: <p>PDF file - 122K</p>