PMID- 24692067 OWN - NLM STAT- MEDLINE DCOM- 20140925 LR - 20211203 IS - 1460-2180 (Electronic) IS - 0143-3334 (Print) IS - 0143-3334 (Linking) VI - 35 IP - 7 DP - 2014 Jul TI - Loss of glutathione peroxidase 7 promotes TNF-alpha-induced NF-kappaB activation in Barrett's carcinogenesis. PG - 1620-8 LID - 10.1093/carcin/bgu083 [doi] AB - 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-kappaB) 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-alpha (TNF-alpha)-induced NF-kappaB transcriptional activity (P < 0.01) and nuclear translocation of NF-kappaB-p65 (P = 0.01). In addition, we detected a marked reduction in phosphorylation levels of components of NF-kappaB signaling pathway, p-p65 (S536), p-IkappaB-alpha (S32) and p-IKKalpha/beta (S176/180), as well as significant suppression in induction of NF-kappaB target genes [TNF-alpha, interleukin (IL)-6, IL-8, IL-1beta, CXCL-1 and CXCL-2] following treatment with TNF-alpha 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-kappaB 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-kappaB. We concluded that the loss of GPX7 expression is a critical step in promoting the TNF-alpha-induced activation of proinflammatory NF-kappaB signaling, a major player in GERD-associated Barrett's carcinogenesis. CI - (c) The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Peng, Dun-Fa AU - Peng DF AD - Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. FAU - Hu, Tian-Ling AU - Hu TL AD - Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN 37232, USA and. FAU - Soutto, Mohammed AU - Soutto M AD - Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA, Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN 37232, USA and. FAU - Belkhiri, Abbes AU - Belkhiri A AD - Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. FAU - El-Rifai, Wael AU - El-Rifai W AD - 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. LA - eng GR - DK058404/DK/NIDDK NIH HHS/United States GR - P30 CA68485/CA/NCI NIH HHS/United States GR - P50 CA95103/CA/NCI NIH HHS/United States GR - R01CA106176/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20140401 PL - England TA - Carcinogenesis JT - Carcinogenesis JID - 8008055 RN - 0 (NF-kappa B) RN - 0 (RNA, Messenger) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Oxygen Species) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Receptors, Tumor Necrosis Factor, Type II) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 1.11.1.- (Peroxidases) RN - EC 1.11.1.9 (GPX7 protein, human) RN - EC 1.11.1.9 (Glutathione Peroxidase) SB - IM MH - Adenocarcinoma/genetics/metabolism/*pathology MH - Barrett Esophagus/genetics/metabolism/*pathology MH - Blotting, Western MH - Cell Transformation, Neoplastic/genetics/metabolism/*pathology MH - Cells, Cultured MH - Esophageal Neoplasms/genetics/metabolism/*pathology MH - Fluorescent Antibody Technique MH - Glutathione Peroxidase MH - Humans MH - NF-kappa B/genetics/*metabolism MH - Peroxidases/antagonists & inhibitors/genetics/*metabolism MH - RNA, Messenger/genetics MH - RNA, Small Interfering/genetics MH - Reactive Oxygen Species/metabolism MH - Real-Time Polymerase Chain Reaction MH - Receptors, Tumor Necrosis Factor, Type I/genetics/metabolism MH - Receptors, Tumor Necrosis Factor, Type II/genetics/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Signal Transduction/drug effects MH - Tumor Necrosis Factor-alpha/*pharmacology PMC - PMC4076814 EDAT- 2014/04/03 06:00 MHDA- 2014/09/26 06:00 PMCR- 2015/07/01 CRDT- 2014/04/03 06:00 PHST- 2014/04/03 06:00 [entrez] PHST- 2014/04/03 06:00 [pubmed] PHST- 2014/09/26 06:00 [medline] PHST- 2015/07/01 00:00 [pmc-release] AID - bgu083 [pii] AID - 10.1093/carcin/bgu083 [doi] PST - ppublish SO - Carcinogenesis. 2014 Jul;35(7):1620-8. doi: 10.1093/carcin/bgu083. Epub 2014 Apr 1.