title: Loss of glutathione peroxidase 7 promotes TNF-α-induced NF-κB activation in Barrett's carcinogenesis.
abstract: 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-κB) 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-α (TNF-α)-induced NF-κB transcriptional activity (P < 0.01) and nuclear translocation of NF-κB-p65 (P = 0.01). In addition, we detected a marked reduction in phosphorylation levels of components of NF-κB signaling pathway, p-p65 (S536), p-IκB-α (S32) and p-IKKα/β (S176/180), as well as significant suppression in induction of NF-κB target genes [TNF-α, interleukin (IL)-6, IL-8, IL-1β, CXCL-1 and CXCL-2] following treatment with TNF-α 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-κB 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-κB. We concluded that the loss of GPX7 expression is a critical step in promoting the TNF-α-induced activation of proinflammatory NF-κB signaling, a major player in GERD-associated Barrett's carcinogenesis.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Dun-Fa
authors.initials: DF
authors.lastname: Peng
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN 37232, USA and.
authors.forename: Tian-Ling
authors.initials: TL
authors.lastname: Hu
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN 37232, USA and.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soutto
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN 37232, USA and Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA wael.el-rifai@vanderbilt.edu.
authors.forename: Wael
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001471:Barrett Esophagus / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D005979:Glutathione Peroxidase; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010544:Peroxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D010544:Peroxidases; C558641:GPX7 protein, human; D005979:Glutathione Peroxidase