Dataset Information

Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis.

ABSTRACT: Esophageal adenocarcinoma (EAC) is the most frequent malignancy in the esophagus in the US and its incidence has been rising rapidly in the past few decades. Chronic gastroesophageal reflux disease (GERD), where the esophageal epithelium is abnormally exposed to acid and bile salts, is a pro-inflammatory condition that is the main risk factor for the development of Barrett's esophagus (BE) and its progression to EAC. Glutathione peroxidase 7 (GPX7) is frequently silenced through DNA hypermethylation during Barrett's tumorigenesis. In this study, we investigated the role of GPX7 in regulating the bile salts-induced inflammatory signaling in Barrett's carcinogenesis. Using quantitative real-time PCR (qRT-PCR), we demonstrated a significant induction in the expression levels of pro-inflammatory cytokines (TNF-?, IL-1?, IL-6, and IL-8) and chemokines (CXCL-1 and CXCL-2) in esophageal cells after exposure to acidic (pH4) or neutral (pH7) bile salts. Western blot analysis showed that exposure to acidic and neutral bile salts increased p-NF-?B-p65 (S536) protein levels independent of ROS. Reconstitution of GPX7 expression in EAC cells abolished the increase of p-p65 (S536) protein levels and mRNA expression of cytokines and chemokines upon treatment with acidic and neutral bile salts. Examination of human primary EAC tissues by qRT-PCR demonstrated significant overexpression of cytokines (TNF-?, IL-1? and IL-8) in EAC samples, as compared to normal samples, with significant inverse correlation with GPX7 expression level. Taken together, the loss of GPX7 expression promotes bile salt-induced activation of pro-inflammatory cytokines and chemokines; important contributors to GERD-associated Barrett's carcinogenesis.

SUBMITTER: Peng DF

PROVIDER: S-EPMC4067510 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis.

Peng Dun-Fa DF Hu Tian-Ling TL Soutto Mohammed M Belkhiri Abbes A El-Rifai Wael W

Journal of Cancer 20140610 7

Esophageal adenocarcinoma (EAC) is the most frequent malignancy in the esophagus in the US and its incidence has been rising rapidly in the past few decades. Chronic gastroesophageal reflux disease (GERD), where the esophageal epithelium is abnormally exposed to acid and bile salts, is a pro-inflammatory condition that is the main risk factor for the development of Barrett's esophagus (BE) and its progression to EAC. Glutathione peroxidase 7 (GPX7) is frequently silenced through DNA hypermethyla ...[more]

PMID: 24963355

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Project description:Esophageal adenocarcinoma (EAC) is a classic example of inflammation-associated cancer, which develops through GERD (gastroesophageal reflux disease)-Barrett's esophagus (BE)-dysplasia-adenocarcinoma sequence. The incidence of EAC has been rising rapidly in the USA and Western countries during the last few decades. The functions of glutathione peroxidase 7 (GPX7), an antioxidant enzyme frequently silenced during Barrett's tumorigenesis, remain largely uncharacterized. In this study, we investigated the potential role of GPX7 in regulating nuclear factor-kappaB (NF-?B) activity in esophageal cells. Western blot analysis, immunofluorescence and luciferase reporter assay data indicated that reconstitution of GPX7 expression in CP-A (non-dysplastic BE cells) and FLO-1 (EAC cells) abrogated tumor necrosis factor-? (TNF-?)-induced NF-?B transcriptional activity (P < 0.01) and nuclear translocation of NF-?B-p65 (P = 0.01). In addition, we detected a marked reduction in phosphorylation levels of components of NF-?B signaling pathway, p-p65 (S536), p-I?B-? (S32) and p-IKK?/? (S176/180), as well as significant suppression in induction of NF-?B target genes [TNF-?, interleukin (IL)-6, IL-8, IL-1?, CXCL-1 and CXCL-2] following treatment with TNF-? in GPX7-expressing FLO-1 cells as compared with control cells. We validated these effects by knockdown of GPX7 expression in HET1A (normal esophageal squamous cells). We found that GPX7-mediated suppression of NF-?B is independent of reactive oxygen species level and GPX7 antioxidant function. Further mechanistic investigations demonstrated that GPX7 promotes protein degradation of TNF-receptor 1 (TNFR1) and TNF receptor-associated factor 2 (TRAF2), suggesting that GPX7 modulates critical upstream regulators of NF-?B. We concluded that the loss of GPX7 expression is a critical step in promoting the TNF-?-induced activation of proinflammatory NF-?B signaling, a major player in GERD-associated Barrett's carcinogenesis.

Project description:Metformin is a traditional anti-hyperglycemic medication that has recently been shown to benefit vascular complications of diabetes via an anti-inflammatory mechanism other than glycemic control. This study aims to test the hypothesis that metformin suppresses diabetic retinopathy (DR) associated intraocular inflammation. Human vitreous from control and proliferative diabetic retinopathy (PDR) patients with or without long-term metformin treatment (> 5 years) were collected for multiple inflammatory cytokines measurements with a cytokine array kit. The vast majority of the measurable cytokines in PDR vitreous has a lower level in metformin group than non-metformin group. Although the p values are not significant due to a relatively small sample size and large deviations, the 95% confidence interval (CI) for the mean difference between the two groups shows some difference in the true values should not be neglected. Using quantitative ELISA, soluble intercellular adhesion molecule -1 (ICAM-1) and monocyte chemoattractant protein -1 (MCP-1) presented with significantly lower concentrations in metformin group versus non-metformin group. Metformin group also has significantly less up-regulated cytokines and diminished positive correlations among the cytokines when compared to non-metformin group. Possible role of AMP-activated protein kinase (AMPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in metformin's anti-inflammatory effects were studied in human retinal vascular endothelial cells (hRVECs) cultured in normal glucose (NG) and high glucose (HG) conditions. Metformin inhibited HG-induced ICAM-1, IL-8, and MCP-1 via AMPK activation, whereas pharmacological AMPK inhibition had no effect on its inhibition of NF-κB p65, sICAM-1, and tumor necrosis factor-α (TNF-α). Metformin-induced suppression of the inflammatory cytokines could also be mediated through its direct inhibition of NF-κB, independent of AMPK pathway. This is a proof-of-concept study that found metformin treatment was associated with reduced inflammatory responses in vitreous of diabetes patients and retinal vascular endothelial cells, supporting the rationale for using metformin to treat DR at an early stage.

Project description:The well-recognized cell phenotypic heterogeneity in tumors is a great challenge for cancer treatment. Dynamic interconversion and movement within a spectrum of different cell phenotypes (cellular plasticity) with the acquisition of specific cell functions is a fascinating biological puzzle, that represent an additional difficulty for cancer treatment and novel therapies development. The understanding of the molecular mechanisms responsible for moving or stabilizing tumor cells within this spectrum of variable states constitutes a valuable tool to overcome these challenges. In particular, cell transitions between epithelial and mesenchymal phenotypes (EMT-MET) and de-and trans-differentiation processes are relevant, since it has been shown that they confer invasiveness, drug resistance, and metastatic ability, due to the simultaneous acquisition of stem-like cell properties. Multiple drivers participate in these cell conversions events. In particular, cellular senescence and senescence-associated soluble factors have been shown to unveil stem-like cell properties and cell plasticity. By modulating gradually the composition of their secretome and the time of exposure, senescent cells may have differential effect not only on tumor cells but also on surrounding cells. Intriguingly, tumor cells that scape from senescence acquire stem-like cell properties and aggressiveness. The reinforcement of senescence and inflammation by soluble factors and the participation of immune cells may provide a dynamic milieu having varied effects on cell transitions, reprogramming, plasticity, stemness and therefore heterogeneity. This will confer different epithelial/mesenchymal traits (hybrid phenotype) and stem-like cell properties, combinations of which, in a particular cell context, could be responsible for different cellular functions during cancer progression (survival, migration, invasion, colonization or proliferation). Additionally, cooperative behavior between cell subpopulations with different phenotypes/stemness functions could also modulate their cellular plasticity. Here, we will discuss the role of senescence and senescence-associated pro-inflammatory cytokines on the induction of cellular plasticity, their effect role in establishing particular states within this spectrum of cell phenotypes and how this is accompanied by stem-like cell properties that, as the epithelial transitions, may also have a continuum of characteristics providing tumor cells with functional adaptability specifically useful in the different stages of carcinogenesis.

Dataset Information

Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis.

Publications

Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis.

Similar Datasets

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