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Background: Glutathione peroxidase 2 (GPX2) is an antioxidant enzyme with an important role in tumor progression in various cancers. However, the clinical significance of GPX2 in lung adenocarcinoma has not been clarified. Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze GPX2 mRNA expression. Then, we conducted immunohistochemistry (IHC) to assess GPX2 expression in specimens acquired from 351 patients with lung adenocarcinoma who underwent surgery at Kyushu University from 2003 to 2012. We investigated the association between GPX2 expression and clinicopathological characteristics and further analyzed the prognostic relevance. Results: qRT-PCR revealed that GPX2 mRNA expression was notably higher in tumor cells than in normal tissues. IHC revealed that high GPX2 expression (n = 175, 49.9%) was significantly correlated with male sex, smoking, advanced pathological stage, and the presence of pleural, lymphatic, and vascular invasion. Patients with high GPX2 expression exhibited significantly shorter recurrence-free survival (RFS) and overall survival. Multivariate analysis identified high GPX2 expression as an independent prognostic factor of RFS. Conclusions: GPX2 expression was significantly associated with pathological malignancy. It is conceivable that high GPX2 expression reflects tumor malignancy. Therefore, high GPX2 expression is a significant prognostic factor of poor prognosis for completely resected lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Objectives: Cholangiocarcinoma (CCA) is a rare tumor with a poor prognosis and poses significant therapeutic challenges. Herein, we investigated the mechanism of efficacy of 125I seed implantation therapy in CCA, focusing on the induction of reactive oxygen species (ROS)-mediated apoptosis and the involvement of glutathione peroxidase 2 (GPX2). Materials and methods: Human cholangiocarcinoma cell lines QBC939 and RBE were purchased for in vitro studies. In vivo studies were performed using a rabbit VX2 CCA model. Apoptosis and proliferation were detected by TUNEL staining and clone formation, respectively. ROS generation was detected by dihydroethidium staining. Histological evaluation was performed by hematoxylin and eosin staining. Protein expression was determined by Western blotting and immunohistochemistry. Results: Our results demonstrate that 125I seeds effectively inhibited tumor growth in the rabbit VX2 tumor model and promoted the apoptosis of CCA cells in vitro in a dose-dependent manner. Molecular analyses indicate a marked increase in reactive oxygen species (ROS) levels following treatment with 125I seeds, suggesting the involvement of ROS-mediated apoptosis in the therapeutic mechanism. Furthermore, the downregulation of glutathione peroxidase 2 (GPX2) was observed, indicating its potential role in modulating ROS-mediated apoptosis in CCA. Conclusion: 125I seed implantation therapy exerts therapeutic effects on CCA by inducing ROS-mediated apoptosis. The downregulation of GPX2 may contribute to enhanced ROS accumulation and apoptotic cell death. These findings provide mechanistic insights into the therapeutic potential of 125I seed implantation for CCA and highlight ROS-mediated apoptosis and GPX2 regulation as promising targets for further investigation and therapeutic intervention in this malignancy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Therapies for diffuse large B-cell lymphoma (DLBCL) are limited due to the diverse gene expression profiles and complicated immune microenvironments, making it an aggressive lymphoma. Beyond this, researches have shown that ferroptosis contributes to tumorigenesis, progression, and metastasis. We thus are interested to dissect the connection between ferroptosis and disease status of DLBCL. We aim at generating a valuable prognosis gene signature for predicting the status of patients of DLBCL, with focus on ferroptosis-related genes (FRGs). OBJECTIVE: To examine the connection between ferroptosis-related genes (FRGs) and clinical outcomes in DLBCL patients based on public datasets. METHODS: An expression profile dataset for DLBCL was downloaded from GSE32918 (https://www.ncbi.nlm.nih.gov/geo/ query/acc.cgi?acc=gse32918), and a ferroptosis-related gene cluster was obtained from the FerrDb database (http://www. zhounan.org/ferrdb/). A prognostic signature was developed from this gene cluster by applying a least absolute shrinkage and selection operator (LASSO) Cox regression analysis to GSE32918, followed by external validation. Its effectiveness as a biomarker and the prognostic value was determined by a receiver operator characteristic curve mono factor analysis. Finally, functional enrichment was evaluated by the package Cluster Profiler of R. RESULTS: Five ferroptosis-related genes (FRGs) (GOP1, GPX2, SLC7A5, ATF4, and CXCL2) associated with DLBCL were obtained by a multivariate analysis. The prognostic power of these five FRGs was verified by TCGA (https://xenabrowser.net/datapages/?dataset=TCGA.DLBC.sampleMap%2FHiSeqV2%5fPANCAN&host=https%3A%2F%2Ftcga.xenahubs.net&removeHub=https%3A%2F%2Fxena.treehouse.gi.ucsc.edu%3A44) and GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=gse 32918) datasets, with ROC analyses. KEGG and GO analyses revealed that upregulated genes in the high-risk group based on the gene signature were enriched in receptor interactions and other cancer-related pathways, including pathways related to abnormal metabolism and cell differentiation. CONCLUSION: The newly developed signature involving GOP1, GPX2, SLC7A5, ATF4, and CXCL2 has the potential to serve as a prognostic biomarker. Furthermore, our results provide additional support for the contribution of ferroptosis to DLBCL. [ABSTRACT FROM AUTHOR]

Colorectal carcinoma (CRC) is a common cancer associated with poor prognosis, and cudraflavone C (Cud C) is a natural flavonol with reported anti-CRC capacity. However, the precise mechanisms underlying the anti-CRC effect require further demonstration. The aim of present study was to evaluate the impact of Cud C on the cell viability and apoptosis of CRC cells and to determine the underlying mechanisms. The Human Protein Atlas (THPA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to analyze the expression status of glutathione peroxidase 2 (GPX2) in CRC. Cell viability was examined using cell counting kit-8 (CCK-8) assay. Flow cytometry was utilized to evaluate apoptosis. The levels of gene transcription and protein expression of GPX2, caspase-3, cleaved caspase-3), β-catenin, and c-Myc were determined by RT-qPCR and Western blotting. Our results showed that GPX2 was overexpressed in CRC as compared to normal tissue and the extent of GPX2 overexpression is greatest in CRC when compared with other cancers according to GEPIA and THPA databases. GPX2 knockdown significantly suppressed the cell viability, induced apoptosis of CRC cell lines, and restrained the activity of Wnt/β-catenin pathway. Cud C treatment decreased cell viability, induced apoptosis in CRC cell lines, and diminished the expression level of GPX2-dependent activation of Wnt/β-catenin pathway, while such effects can be abolished by GPX2 overexpression. In conclusion, Cud C suppressed GPX2-dependent Wnt/β-catenin pathway to exert anti-CRC function. [ABSTRACT FROM AUTHOR]

Head and neck cancer (HNC) ranks among the top ten prevalent cancers worldwide. Radiotherapy stands as a pivotal treatment component for HNC; however, radioresistance in cancerous cells often leads to local recurrence, becoming a substantial factor in treatment failure. MicroRNAs (miRNAs) are compact, non-coding RNAs that regulate gene expression by targeting mRNAs to inhibit protein translation. Although several studies have indicated that the dysregulation of miRNAs is intricately linked with malignant transformation, understanding this molecular family's role in radioresistance remains limited. This study determined the role of miR-630 in regulating radiosensitivity in HNC. We discovered that miR-630 functions as an oncomiR, marked by its overexpression in HNC patients, correlating with a poorer prognosis. We further delineated the malignant function of miR-630 in HNC cells. While it had a minimal impact on cell growth, the miR-630 contributed to radioresistance in HNC cells. This result was supported by decreased cellular apoptosis and caspase enzyme activities. Moreover, miR-630 overexpression mitigated irradiation-induced DNA damage, evidenced by the reduced levels of the γ-H2AX histone protein, a marker for double-strand DNA breaks. Mechanistically, the overexpression of miR-630 decreased the cellular ROS levels and initiated Nrf2 transcriptional activity, resulting in the upregulation of the antioxidant enzyme GPX2. Thus, this study elucidates that miR-630 augments radioresistance by inducing an anti-apoptotic effect via the Nrf2–GPX2 molecular axis in HNC. The modulation of miR-630 may serve as a novel radiosensitizing target for HNC. [ABSTRACT FROM AUTHOR]

Recent research on selenium-dependent glutathione peroxidase 2 (GPX2) tends to focus on possible roles in tumorigenesis. This is based on the idea that normally generated hydroperoxide species can damage DNA to produce mutations and react with protein sulfhydryl groups to perturb normal regulation of cancer-related pathways. GPX2 is one of many peroxidases available to control hydroperoxide levels. Altered GPX2 expression levels from normal to cancer or with cancer stages seems to be the main feature in bringing it to the attention of investigators. In this commentary, we examine this premise as a basis for cancer studies, largely by trying to place GPX2 within the larger context of antioxidant enzyme gene expression. We make use of public databases and illustrate their possible role in approaching this issue. Since use of such databases is new to us, we looked to sources in the literature to evaluate expression level data, finding general agreement with some discrepancies over the range of expression and relative expression levels among some samples. Using the database information, we critically evaluate methods used to study GPX2 in the current literature for a variety of cancers. Second, groups are now trying to compare enzymatic properties of GPX1 and GPX2 using proteins from bacterial cultures. We weigh in on these recent findings and discuss the impact on the relative GPX2 and GPX1 functions. [ABSTRACT FROM AUTHOR]

Recent research on selenium-dependent glutathione peroxidase 2 (GPX2) tends to focus on possible roles in tumorigenesis. This is based on the idea that normally generated hydroperoxide species can damage DNA to produce mutations and react with protein sulfhydryl groups to perturb normal regulation of cancer-related pathways. GPX2 is one of many peroxidases available to control hydroperoxide levels. Altered GPX2 expression levels from normal to cancer or with cancer stages seems to be the main feature in bringing it to the attention of investigators. In this commentary, we examine this premise as a basis for cancer studies, largely by trying to place GPX2 within the larger context of antioxidant enzyme gene expression. We make use of public databases and illustrate their possible role in approaching this issue. Since use of such databases is new to us, we looked to sources in the literature to evaluate expression level data, finding general agreement with some discrepancies over the range of expression and relative expression levels among some samples. Using the database information, we critically evaluate methods used to study GPX2 in the current literature for a variety of cancers. Second, groups are now trying to compare enzymatic properties of GPX1 and GPX2 using proteins from bacterial cultures. We weigh in on these recent findings and discuss the impact on the relative GPX2 and GPX1 functions.

Abstract Lung cancer, with non‐small cell lung cancer (NSCLC) being the main subtype, is the leading cause of cancer death worldwide, which is mainly due to the cancer metastasis. Glutathione peroxidase 2 (GPX2), an antioxidant enzyme, is involved in tumor progression and metastasis. Nevertheless, the role of GPX2 in NSCLC metastasis has not been clarified. In this study, we found that GPX2 expression was elevated in NSCLC tissues and high GPX2 expression was correlated with poor prognosis in patients with NSCLC. In addtion, GPX2 expression was related to the patient's clinicopathological features, including lymph node metastasis, tumor size, and TNM stage. Overexpression of GPX2 promoted epithelial–mesenchymal transition (EMT), migration, and invasion of NSCLC cells in vitro. Knockdown of GPX2 showed the opposite effects in vitro and inhibited the metastasis of NSCLC cells in nude mice. Furthermore, GPX2 reduced reactive oxygen species (ROS) accumulation and activated the PI3K/AKT/mTOR/Snail signaling axis. Therefore, our results indicate that GPX2 promotes EMT and metastasis of NSCLC cells by activating the PI3K/AKT/mTOR/Snail signaling axis via the removal of ROS. GPX2 may be an effective diagnostic and prognostic biomarker for NSCLC.

Background. Metabolic reprogramming is a key marker in the occurrence and development of tumors. This process generates more reactive oxygen species (ROS), promoting the development of oxidative stress. To prevent ROS from harming tumor cells, tumor cells can increase the production of reducing agents to counteract excessive ROS. NMRAL2P has been shown to promote the production of reductive mRNA and plays an important role in the process of oxidative stress. Methods. In this study, the clinical data and RNA sequencing of head and neck tumors were obtained from The Cancer Genome Atlas data set. The long non-coding RNA (LncRNA) related to oxidative stress were then identified using differential and correlation analyses. The differential expression and prognosis of the identified lncRNA were then verified using samples from the library of the Second Hospital of Hebei Medical University. Only NMRAL2P was substantially expressed in cancer tissues and predicted a poor prognosis. The tumor-promoting impact of NMRAL2P was then confirmed using in vitro functional assays. The data set was then split into highand low-expression subgroups based on the median gene expression of NMRAL2P to obtain the mRNA that had a large difference between the two groups, and examine the mechanism of NMRAL2P on GPX2 using quantitative real-time PCR, RNA binding protein immunoprecipitation assay, and chromatin immunoprecipitation. Mass spectrometry was used to identify NMRAL2P-binding proteins and western blotting was used to investigate probable mechanisms. Results. The lncRNA NMRAL2P is associated with oxidative stress in head and neck tumors. In vitro functional assays showed that the gene has a cancer-promoting effect, increasing lactic acid and superoxide dismutase production, and reducing the production of ROS and malondialdehyde. NMRAL2P promotes the transcription of GPX2 by binding to transcription factor Nrf2. The gene also inhibits the degradation of ENO1, a crucial enzyme in glycolysis, by binding to protein ENO1. Conclusions. This study shows that NMRAL2P can promote glycolysis and reduce the harm to tumor cells caused by ROS. The gene can also be used as a possible target for the treatment of head and neck tumors. [ABSTRACT FROM AUTHOR]

Lung cancer, with non‐small cell lung cancer (NSCLC) being the main subtype, is the leading cause of cancer death worldwide, which is mainly due to the cancer metastasis. Glutathione peroxidase 2 (GPX2), an antioxidant enzyme, is involved in tumor progression and metastasis. Nevertheless, the role of GPX2 in NSCLC metastasis has not been clarified. In this study, we found that GPX2 expression was elevated in NSCLC tissues and high GPX2 expression was correlated with poor prognosis in patients with NSCLC. In addtion, GPX2 expression was related to the patient's clinicopathological features, including lymph node metastasis, tumor size, and TNM stage. Overexpression of GPX2 promoted epithelial–mesenchymal transition (EMT), migration, and invasion of NSCLC cells in vitro. Knockdown of GPX2 showed the opposite effects in vitro and inhibited the metastasis of NSCLC cells in nude mice. Furthermore, GPX2 reduced reactive oxygen species (ROS) accumulation and activated the PI3K/AKT/mTOR/Snail signaling axis. Therefore, our results indicate that GPX2 promotes EMT and metastasis of NSCLC cells by activating the PI3K/AKT/mTOR/Snail signaling axis via the removal of ROS. GPX2 may be an effective diagnostic and prognostic biomarker for NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: Lenvatinib has recently become available as the first-line therapy for advanced hepatocellular carcinoma (HCC), but its molecular mechanism in HCC remains largely unknown. Objectives: The current study aims to identify the molecular mechanisms of lenvatinib in HCC. Methods: Gene expression microarrays, flow cytometry, western blot, qRT-PCR, immunohistochemistry and immunofluorescence were used to study the response of HCC cells to lenvatinib. Xenograft tumor of Huh7 cells was also established to detect the effect of lenvatinib in vivo. Results: Herein, we found that lenvatinib could induce apoptosis via increasing reactive oxygen species (ROS) levels in HCC cells. Then, microarray analysis and qRT-PCR results confirmed that GPX2 was a vital target for lenvatinib against HCC. Loss and gain function of experiment showed that regulating GPX2 levels markedly affected the lenvatinib-induced ROS levels and apoptosis in HCC cells. In addition, analyses of The Cancer Genome Atlas database and the qRT-PCR results in our cohort both showed that GPX2 markedly overexpressed in tumor tissues and correlated with poor overall survival in HCC. Mechanistically, our findings further demonstrated that GPX2 was a downstream gene regulated by β-catenin, while lenvatinib could prevent nuclear translocation of β-catenin and further inhibit GPX2 expression in HCC cells. More importantly, the correlation of GPX2 expression with lenvatinib response was further analyzed in 22 HCC patients who received lenvatinib therapy, and the results showed that the objective response rate (ORR) in patients with low GPX2 expression was 44.4% (4/9), while the ORR in patients with high GPX2 levels was only 7.7% (1/13). Conclusion: Our findings indicated that GPX2 plays an important role in lenvatinib-induced HCC cell apoptosis, which might serve as a biomarker for instruction of lenvatinib therapy in HCC patients.

Head and neck cancer (HNC) ranks among the top ten prevalent cancers worldwide. Radiotherapy stands as a pivotal treatment component for HNC; however, radioresistance in cancerous cells often leads to local recurrence, becoming a substantial factor in treatment failure. MicroRNAs (miRNAs) are compact, non-coding RNAs that regulate gene expression by targeting mRNAs to inhibit protein translation. Although several studies have indicated that the dysregulation of miRNAs is intricately linked with malignant transformation, understanding this molecular family’s role in radioresistance remains limited. This study determined the role of miR-630 in regulating radiosensitivity in HNC. We discovered that miR-630 functions as an oncomiR, marked by its overexpression in HNC patients, correlating with a poorer prognosis. We further delineated the malignant function of miR-630 in HNC cells. While it had a minimal impact on cell growth, the miR-630 contributed to radioresistance in HNC cells. This result was supported by decreased cellular apoptosis and caspase enzyme activities. Moreover, miR-630 overexpression mitigated irradiation-induced DNA damage, evidenced by the reduced levels of the γ-H2AX histone protein, a marker for double-strand DNA breaks. Mechanistically, the overexpression of miR-630 decreased the cellular ROS levels and initiated Nrf2 transcriptional activity, resulting in the upregulation of the antioxidant enzyme GPX2. Thus, this study elucidates that miR-630 augments radioresistance by inducing an anti-apoptotic effect via the Nrf2–GPX2 molecular axis in HNC. The modulation of miR-630 may serve as a novel radiosensitizing target for HNC.

[Display omitted] • Lenvatinib inhibits GPX2 expression and induces ROS related apoptosis in HCC. • High expression of GPX2 is an independent risk factor for overall survival in HCC. • Lenvatinib induces cell apoptosis through inhibiting β-catenin/GPX2 axis in HCC. • GPX2 levels could predict lenvatinib sensibility for HCC patients. Lenvatinib has recently become available as the first-line therapy for advanced hepatocellular carcinoma (HCC), but its molecular mechanism in HCC remains largely unknown. The current study aims to identify the molecular mechanisms of lenvatinib in HCC. Gene expression microarrays, flow cytometry, western blot, qRT-PCR, immunohistochemistry and immunofluorescence were used to study the response of HCC cells to lenvatinib. Xenograft tumor of Huh7 cells was also established to detect the effect of lenvatinib in vivo. Herein, we found that lenvatinib could induce apoptosis via increasing reactive oxygen species (ROS) levels in HCC cells. Then, microarray analysis and qRT-PCR results confirmed that GPX2 was a vital target for lenvatinib against HCC. Loss and gain function of experiment showed that regulating GPX2 levels markedly affected the lenvatinib-induced ROS levels and apoptosis in HCC cells. In addition, analyses of The Cancer Genome Atlas database and the qRT-PCR results in our cohort both showed that GPX2 markedly overexpressed in tumor tissues and correlated with poor overall survival in HCC. Mechanistically, our findings further demonstrated that GPX2 was a downstream gene regulated by β-catenin, while lenvatinib could prevent nuclear translocation of β-catenin and further inhibit GPX2 expression in HCC cells. More importantly, the correlation of GPX2 expression with lenvatinib response was further analyzed in 22 HCC patients who received lenvatinib therapy, and the results showed that the objective response rate (ORR) in patients with low GPX2 expression was 44.4% (4/9), while the ORR in patients with high GPX2 levels was only 7.7% (1/13). Our findings indicated that GPX2 plays an important role in lenvatinib-induced HCC cell apoptosis, which might serve as a biomarker for instruction of lenvatinib therapy in HCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Glutathione peroxidase 2 (GPX2) gene expression differs between individuals with different GPX2 polymorphism. Individuals with high GPX2 expression had thinning 100 kg backfat (BF) thickness, no change on average daily gain (AG) and lower feed conversion ratio (FCR) and residual feed intake (RFI) in Duroc pigs. The reason for this result could be that increasing GPX2 could inhibit the adipocyte proliferation and differentiation, promoting the lipid degradation. Meanwhile, GPX2 may promote muscle cells' proliferation and myogenic differentiation. Overall, our fundings indicate that GPX2 can transfer more nutrients to less fat deposition direction, providing the material basis for animal weight gain. GPX2 has been recognized as a potential candidate gene for feed efficiency in pigs. This article aimed to elucidate polymorphism of GPX2 associated with feed efficiency and its related molecular mechanism. In this study, seven single nucleotide polymorphisms (SNP) of GPX2 were found among 383 Duroc pigs. In addition, seven SNPs and ALGA0043483 (PorcineSNP60 BeadChip data in 600 Duroc pigs), which are near the GPX2 gene, were identified in one haplotypes block. Furthermore, associated studies showed that the genotype of GPX2 has significant association with weaning weight and 100 kg BF in Duroc pigs. In addition, the AG had no effect when the backfat became thinner, and the FCR and RFI traits had a tendency to decrease in the G3 + TT combination genotype, accompanied by an increase of GPX2 expression in backfat and muscle tissues. At the cellular level, the adipocyte proliferation and ability of adipogenic differentiation were reduced, and the lipid degradation increased in 3T3-L1 when there was overexpression of GPX2. In contrast, overexpression of the GPX2 gene can promote the muscle cell proliferation and myogenic differentiation in C2C12 cells. In other words, GPX2 has the effect of reducing fat deposition and promoting muscle development, and it is a candidate gene for backfat and feed efficiency. [ABSTRACT FROM AUTHOR]

Objective. This study aimed to establish a prognostic model related to prostate cancer (PCa) recurrence-free survival (RFS) and identify biomarkers. Methods. The RFS prognostic model and key genes associated with PCa were es- tablished using Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression from the Cancer Genome Atlas (TCGA)-PRAD and the Gene Expression Omnibus (GEO) GSE46602 datasets. The weighted gene co-expression network (WGCNA) was used to analyze the obtained key modules and genes, and gene set enrichment analysis (GSEA) was performed. The phenotype and mechanism were verified in vitro. Results. A total of 18 genes were obtained by LASSO regression, and an RFS model was established and verified (TCGA, AUC: 0.774; GSE70768, AUC: 0.759). Three key genes were obtained using multivariate Cox regression. WGCNA analysis obtained the blue module closely related to the Gleason score (cor = -0.22, P =3.3e-05) and the unique gene glutathione peroxidase 2 (GPX2). Immunohistochemical analysis showed that the expression of GPX2 was significantly higher in patients with PCa than in patients with benign prostatic hyperplasia (P <0.05), but there was no significant correlation with the Gleason score (GSE46602 and GSE6919 verified), which was also verified in the GSE46602 and GSE6919 datasets. The GSEA results showed that GPX2 expression was mainly related to the epithelial-mesenchymal transition (EMT) and Wnt pathways. Additionally, GPX2 expression significantly correlated with eight kinds of immune cells. In human PCa cell lines LNCaP and 22RV1, si-GPX2 inhibited proliferation and invasion, and induced apoptosis when compared with si-NC. The protein expression of Wnt3a, glycogen synthase kinase 3β (GSK3β), phosphorylated (p)-GSK3β, β-catenin, p-β-catenin, c-myc, cyclin D1, and vimentin decreased; the expression of E-cadherin increased; and the results for over-GPX2 were opposite to those for over-NC. The protein expression of GPX2 decreased, and β-catenin was unchanged in the si-GPX2+ SKL2001 group compared with the si-NC group. Conclusion. We successfully constructed the PCa RFS prognostic model, obtained RFS-related biomarker GPX2, and found that GPX2 regulated PCa progression and triggered Wnt/β-catenin/EMT pathway molecular changes. [ABSTRACT FROM AUTHOR]

We published the first paper to characterize GPX2 (aka GSHPx-GI) as a selenoenzyme with glutathione peroxidase activity in 1993. Among the four Se-GPX isozymes, GPX1-4, GPX1 and GPX2 are closely related in terms of structure, substrate specificities, and subcellular localization. What sets them apart are distinct patterns of gene regulation, tissue distribution and response to selenium. While we identified the digestive tract epithelium as the main site of GPX2 expression, later work has shown GPX2 is found more widely in epithelial tissues with concentration of expression in stem cell and proliferative compartments. GPX2 expression is regulated over a wide range of levels by many pathways, including NRF2, WNT, p53, RARE and this often results in attaching undue significance to GPX2 as GPX2 is only a part of a system of hydroperoxidase activities, including GPX1, peroxiredoxins and catalase. These other activities may play equal or greater roles, particularly in cell lines cultured without selenium supplementation and often with very low GPX2 levels. This could be assessed by examining levels of mRNA and protein among these various peroxidases at the outset of studies. As an example, it was found that GPX1 responds to the absence of GPX2 in mouse ileum and colon epithelium with higher expression. As such, both Gpx1 and Gpx2 had to be knocked out in mice to produce ileocolitis. However, we note that the actual role of GPX1 and GPX2 in relation to peroxiredoxin function is unclear. There may be an interdependence that requires only low amounts of GPX1 and/or GPX2 in a supporting role to maintain proper peroxiredoxin function. GPX2 levels may be prognostic for cancer progression in colon, breast, prostate and liver, however, there is no consistent trend for higher or lower levels to be favorable. [Display omitted] • GPX2 was discovered by investigators screening human liver cDNA libraries with GPX1 probes. • GPX2 was characterized as a cytoplasmic selenoprotein with GPX activity like GPX1 and high expression in gastrointestinal tract. A role for GPX2 in the crypt/gland regions of the mid-lower GI was indicated by work with GPX1-knockout mice, GPX2-knockout mice and a combination of the lines. • Generally independent regulation and compartmentalization define semi-independent roles for the GPX2 and GPX1 isoenzymes. There is likely interaction in other tissues. • Recent work has broadened the range of tissues with expression with suggestion of impact on tumororigenesis and metastasis. Much work is reported without adequate context for GPX2 as a component of an array of hydroperoxidases and performed under conditions where GPX2 protein levels may be miniscule due to cell line or inadequate selenium. • Possible dominance by GPX2 in basal cell compartments is indicated and represents a possible future direction for GPX2 research. [ABSTRACT FROM AUTHOR]

Background: People with inflammatory bowel disease (IBD) including ulcerative colitis are at risk for colorectal cancer. Despite available effective drugs used to treat IBD, many patients fail or lose response over time with some displaying drug-induced adverse events. Saffron (Crocus sativus) has been reported to have anti-inflammatory properties. Its protective role in IBD has not been explored extensively. Aim: To establish whether saffron treatment alleviates inflammation in experimental colitis. Methods: Colitis was induced in C57BL/6 mice with 3% DSS and treated with either saffron doses (7.5, 15, 20, 25 mg/kg body weight) or vehicle through daily gavage. On day 11, mice were euthanized and analyzed for gross and microscopic inflammation. Distal colon segments were collected for mRNA and protein expression of HO-1 protein and GPX2, (the downstream targets of NRF-2). Nrf-2 translocation from cytosol to nucleus was confirmed by immunofluorescence, and further Nrf-2 protein expression in nuclear and cytosolic fraction of colon was analyzed by immunoblot. Immune cells were isolated from the lamina propria of mouse colon for flow cytometry-based immunophenotyping. Colitis was also induced in C57BL/6 Ahr knockout and wild type mice to explore the involvement of Ahr-dependent pathways in saffron's protective effect(s). The therapeutic effect of saffron was further validated in another TNBS model of colitis. Results: Saffron 20 mg/kg body weight showed improved colon gross and histology features and led to better body weight, colon length, histology score, and reduced disease activity index (DAI). Saffron significantly decreased pro-inflammatory macrophages (M1), while increasing anti-inflammatory macrophages (M2) and IL10 + dendritic cells. Saffron treatment also enhanced CD3 + T and CD3 + CD8 + T cells followed by increase in different CD3 + CD4 + T cells subsets like CD25 + T cells, FoxP3 + CD25 + regulatory T cells, and CD4 + FOXP3 + CD25-regulatory T cells. Immunoblot analysis showed a significant increase in HO-1/GPX2 protein expression. With saffron treatment, Nrf-2 translocation into nucleus from cytosol also supports the involvement of Nrf-2 and its downstream targets in the protective effect of saffron. Further, we demonstrated that saffron in part exert anti-inflammatory effect through activation of aryl hydrocarbon receptor (AhR)-nuclear factor erythroid 2–related factor 2 (Nrf2)-dependent pathways. Conclusion: These data demonstrate saffron's therapeutic potential and its protective role in part via Ahr/Nrf-2 pathways and regulatory innate and adaptive immune cells. [ABSTRACT FROM AUTHOR]

Metabolic enzyme-genes (MEs) play critical roles in various types of cancers. However, MEs have not been systematically and thoroughly studied in pancreatic cancer (PC). Global analysis of MEs in PC will help us to understand PC progressing and provide new insights into PC therapy. In this study, we systematically analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) (n = 180 + 4) and GSE15471 (n = 36 + 36) and discovered that metabolic pathways are disordered in PC. Co-expression network modules of MEs were constructed using weighted gene co-expression network analysis (WGCNA), which identified two key modules. Both modules revealed that the glutathione signaling pathway is disordered in PC and correlated with PC stages. Notably, glutathione peroxidase 2 (GPX2), an important gene involved in glutathione signaling pathway, is a hub gene of the key modules. Analysis of immune microenvironment components reveals that PC stage is associated with M2 macrophages, the marker gene of which is significantly correlated with GPX2. The results indicated that GPX2 is associated with PC progression, providing new insights for future targeted therapy.

Glioblastoma multiforme (GBM) is the leading cause of death among adult brain cancer patients. Glutathione peroxidase 2 (GPX2), as a factor in oxidative stress, plays an important role in carcinogenesis. However, its role in GBM has not been well established. The study aimed to investigate the clinical significance of GPX2 with GBM prognosis.

The main alterations of osteoarthritis are degenerative lesions of articular cartilage and secondary hyperostosis. Despite the unclear pathogenic mechanism, experimental studies have confirmed that the incidence of osteoarthritis is closely associated with inflammation-related substances. In this study, we explored the significance of serum GPX2 levels in patients with osteoarthritis and the mechanism of GPX2 in the anti-inflammation effects in osteoarthritis. As a result, serum GPX2 level was down-regulated and there was a negative correlation between GPX2 levels and IL-1β levels in patients with osteoarthritis. Over-expression of GPX2 decreased the inflammatory levels and down-regulation of GPX2 increased inflammatory levels in vitro. In contrast, GPX2 combined and regulated STAT3 protein expression. Over-expression of GPX2 promoted ubiquitination-STAT3 protein expression to decrease p-STAT3 protein expression in vitro. The inhibition of STAT3 attenuated the anti-inflammation effects of GPX2 in osteoarthritis. Thus, we proposed that GPX2 was down-regulated in patients with osteoarthritis and GPX2 played vital roles in osteoarthritis for clinical diagnosis or therapy. [ABSTRACT FROM AUTHOR]

GPX2 has been recognized as a potential candidate gene for feed efficiency in pigs. This article aimed to elucidate polymorphism of GPX2 associated with feed efficiency and its related molecular mechanism. In this study, seven single nucleotide polymorphisms (SNP) of GPX2 were found among 383 Duroc pigs. In addition, seven SNPs and ALGA0043483 (PorcineSNP60 BeadChip data in 600 Duroc pigs), which are near the GPX2 gene, were identified in one haplotypes block. Furthermore, associated studies showed that the genotype of GPX2 has significant association with weaning weight and 100 kg BF in Duroc pigs. In addition, the AG had no effect when the backfat became thinner, and the FCR and RFI traits had a tendency to decrease in the G3 + TT combination genotype, accompanied by an increase of GPX2 expression in backfat and muscle tissues. At the cellular level, the adipocyte proliferation and ability of adipogenic differentiation were reduced, and the lipid degradation increased in 3T3-L1 when there was overexpression of GPX2. In contrast, overexpression of the GPX2 gene can promote the muscle cell proliferation and myogenic differentiation in C2C12 cells. In other words, GPX2 has the effect of reducing fat deposition and promoting muscle development, and it is a candidate gene for backfat and feed efficiency.

Selenoproteins are translated via animal domain-specific elongation machineries that redefine dedicated UGA opal codons from termination of translation to selenocysteine (Sec) insertion, utilizing specific tRNA species and Sec-specific elongation factors. This has made recombinant production of mammalian selenoproteins in E. coli technically challenging but recently we developed a methodology that enables such production, using recoding of UAG for Sec in an RF1-deficient host strain. Here we used that approach for production of the human glutathione peroxidases 1, 2 and 4 (GPX1, GPX2 and GPX4), with all these three enzymes being important antioxidant selenoproteins. Among these, GPX4 is the sole embryonically essential enzyme, and is also known to be essential for spermatogenesis as well as protection from cell death through ferroptosis. Enzyme kinetics, ICP-MS and mass spectrometry analyses of the purified recombinant proteins were used to characterize selenoprotein characteristics and their Sec contents. This revealed a unique phenomenon of one-codon skipping, resulting in a lack of a single amino acid at the position corresponding to the selenocysteine (Sec) residue, in about 30% of the recombinant GPX isoenzyme products. We furthermore confirmed the previously described UAG suppression with Lys or Gln as well as a minor suppression with Tyr, together resulting in about 20% Sec contents in the full-length proteins. No additional frameshifts or translational errors were detected. We subsequently found that Sec-containing GPX4 could be further purified over a bromosulfophthalein-column, yielding purified recombinant GPX4 with close to complete Sec contents. This production method for homogenously purified GPX4 should help to further advance the studies of this important selenoprotein.

The RNA exosome complex targets AU-rich element (ARE)-containing mRNAs in eukaryotic cells. We identified a transcription factor, ZSCAN10, which binds to the promoters of multiple RNA exosome complex subunits in pluripotent stem cells to maintain subunit gene expression. We discovered that induced pluripotent stem cell clones generated from aged tissue donors (A-iPSC) show poor expression of ZSCAN10, leading to poor RNA exosome complex expression, and a subsequent elevation in ARE-containing RNAs, including glutathione peroxidase 2 (Gpx2). Excess GPX2 leads to excess glutathione-mediated reactive oxygen species scavenging activity that blunts the DNA damage response and apoptosis. Expression of ZSCAN10 in A-iPSC recovers RNA exosome gene expression, the DNA damage response, and apoptosis. These findings reveal the central role of ZSCAN10 and the RNA exosome complex in maintaining pluripotent stem cell redox status to support a normal DNA damage response.

Background: We aimed at identifying molecular markers predictive of clinical outcome in patients with head and neck cancer based on the expression profile of cells showing epithelial‐like (EL) or mesenchymal‐like (ML) phenotypes. Materials and methods: We analyzed the association between EL and ML cells and migration, drug resistance, or tumor growth. The differential gene expression profile between cell types was used to build a model to stratify patients according to survival. Results: EL cells were sensitive to cisplatin and cetuximab, showed low migration, and generated squamous differentiated tumors in mouse. A differential 93‐gene expression signature between ML and EL cells was used to build a three‐gene (EFS, GPX2, and SPRR1A) survival model by analyzing the RNA‐seq data of the TCGA‐HNSC project. Its prognostic value was confirmed in two independent cohorts. Conclusion: EFS, GPX2, and SPRR1A are prognostic markers able to distinguish clinical outcome among subtypes sharing an EL phenotype. [ABSTRACT FROM AUTHOR]

Background: Metabolic reprogramming is a key marker in the occurrence and development of tumors. This process generates more reactive oxygen species (ROS), promoting the development of oxidative stress. To prevent ROS from harming tumor cells, tumor cells can increase the production of reducing agents to counteract excessive ROS. NMRAL2P has been shown to promote the production of reductive mRNA and plays an important role in the process of oxidative stress., Methods: In this study, the clinical data and RNA sequencing of head and neck tumors were obtained from The Cancer Genome Atlas data set. The long non-coding RNA (LncRNA) related to oxidative stress were then identified using differential and correlation analyses. The differential expression and prognosis of the identified lncRNA were then verified using samples from the library of the Second Hospital of Hebei Medical University. Only NMRAL2P was substantially expressed in cancer tissues and predicted a poor prognosis. The tumor-promoting impact of NMRAL2P was then confirmed using in vitro functional assays. The data set was then split into high- and low-expression subgroups based on the median gene expression of NMRAL2P to obtain the mRNA that had a large difference between the two groups, and examine the mechanism of NMRAL2P on GPX2 using quantitative real-time PCR, RNA binding protein immunoprecipitation assay, and chromatin immunoprecipitation. Mass spectrometry was used to identify NMRAL2P -binding proteins and western blotting was used to investigate probable mechanisms., Results: The lncRNA NMRAL2P is associated with oxidative stress in head and neck tumors. In vitro functional assays showed that the gene has a cancer-promoting effect, increasing lactic acid and superoxide dismutase production, and reducing the production of ROS and malondialdehyde. NMRAL2P promotes the transcription of GPX2 by binding to transcription factor Nrf2. The gene also inhibits the degradation of ENO1, a crucial enzyme in glycolysis, by binding to protein ENO1., Conclusions: This study shows that NMRAL2P can promote glycolysis and reduce the harm to tumor cells caused by ROS. The gene can also be used as a possible target for the treatment of head and neck tumors., Competing Interests: The authors declare there are no competing interests., (©2023 Nie et al.)

OBJECTIVE: This study was designed to evaluate the relation between GPx2 (glutathione peroxidase 2) expressions and clinicopathological features as well as prognosis of patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 89 cases of NPC were investigated to examine the immunohistochemical expression of GPx2. Fourteen pairs of NPC and the control samples were analyzed respectively by qRT-PCR and Western blot. The correlations of GPx2 expressions with the clinicopathologic features and the prognosis of NPC patients were also analyzed. RESULTS: The expression of GPx2 in NPC tissues was elevated immunohistochemically when compared with normal nasopharyngeal tissues (P < 0.05). The mRNA expression of GPx2 in carcinoma tissues was highly elevated compared with the control tissues (P < 0.05). GPx2 protein in carcinoma tissues was also over expressed than in control tissues (P < 0.05). Also GPx2 expression was significantly higher in the late clinical stage (P = 0.02). While there was no significant association between GPx2 expression and patient age, sex, T-stage, N-stage and the metastasis. CONCLUSIONS: GPx2 may play an important role in the development of nasopharyngeal carcinoma. Furthermore, GPx2 may serve as a prognostic biomarker for NPC patient. [ABSTRACT FROM AUTHOR]

Redox signaling regulates physiological self-renewal, proliferation, migration and differentiation in gastrointestinal epithelium by modulating Wnt/β-catenin and Notch signaling pathways mainly through NADPH oxidases (NOXs). In the intestine, intracellular and extracellular thiol redox status modulates the proliferative potential of epithelial cells. Furthermore, commensal bacteria contribute to intestine epithelial homeostasis through NOX1- and dual oxidase 2-derived reactive oxygen species (ROS). The loss of redox homeostasis is involved in the pathogenesis and development of a wide diversity of gastrointestinal disorders, such as Barrett’s esophagus, esophageal adenocarcinoma, peptic ulcer, gastric cancer, ischemic intestinal injury, celiac disease, inflammatory bowel disease and colorectal cancer. The overproduction of superoxide anion together with inactivation of superoxide dismutase are involved in the pathogenesis of Barrett’s esophagus and its transformation to adenocarcinoma. In Helicobacter pylori -induced peptic ulcer, oxidative stress derived from the leukocyte infiltrate and NOX1 aggravates mucosal damage, especially in HspB+ strains that downregulate Nrf2. In celiac disease, oxidative stress mediates most of the cytotoxic effects induced by gluten peptides and increases transglutaminase levels, whereas nitrosative stress contributes to the impairment of tight junctions. Progression of inflammatory bowel disease relies on the balance between pro-inflammatory redox-sensitive pathways, such as NLRP3 inflammasome and NF-κB, and the adaptive up-regulation of Mn superoxide dismutase and glutathione peroxidase 2. In colorectal cancer, redox signaling exhibits two Janus faces: On the one hand, NOX1 up-regulation and derived hydrogen peroxide enhance Wnt/β-catenin and Notch proliferating pathways; on the other hand, ROS may disrupt tumor progression through different pro-apoptotic mechanisms. In conclusion, redox signaling plays a critical role in the physiology and pathophysiology of gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Background: Chaoshan region, a littoral area of Guangdong province in southern China, has a high incidence of esophageal squamous cell carcinoma (ESCC). At present, the prognosis of ESCC is still very poor, therefore, there is urgent need to seek valuable molecular biomarker for prognostic evaluation to guide clinical treatment. GPX2, a selenoprotein, was exclusively expressed in gastrointestinal tract and has an anti-oxidative damage and anti-tumour effect in the progress of tumourigenesis.Methods: We collected 161 ESCC patients samples, among which 83 patients were followed up. We employed immunochemistry analysis, western blotting and quantitative real-time PCR for measuring the expression of GPX2 within ESCC samples. We analysed the relationship between the expression of GPX2 and clinicopathological parameters of 161 patients with ESCC by Chi-square or Fisher's exact test. The survival analysis of GPX2 expression within ESCC tissues was evaluated by the Kaplan-Meier method and Cox-regression.Results: A significant higher expression level of GPX2 was detected in tumour tissues compared to that in non-tumour tissues (P < 0.001). Moreover, GPX2 expression has statistically significant difference in the tumour histological grade of ESCC (P < 0.001), while there was no statistically significant difference in age, sex, tumour size, tumour location, gross morphology and clinical TNM stages (P > 0.05). Meanwhile, the expression of GPX2 protein was obviously down-regulated within poorly differentiated ESCC. Last, survival analysis revealed that tumour histological grade and clinical TNM stages, both of the clinical pathological parameters of ESCC, were associated with the prognosis of patients with ESCC (respectively, P = 0.009, HR (95 % CI) = 1.885 (1.212 ~ 2.932); P = 0.007, HR (95 % CI) = 2.046 (1.318 ~ 3.177)). More importantly, loss expression of GPX2 protein predicted poor prognosis in patients with ESCC (P < 0.001, HR (95 % CI) = 5.700 (2.337 ~ 13.907)).Conclusions: Collectively, these results suggested that the expression of GPX2 was significantly up-regulated within ESCC tumour tissues. GPX2 might be an important predictor for the prognosis of ESCC and a potential target for intervention and treatment of ESCC. [ABSTRACT FROM AUTHOR]