Loss of glutathione peroxidase 7 promotes TNF-α-induced NF-κB activation in Barrett's carcinogenesis: GPX7 regulates NF-kB

Dun Fa Peng, Tian Ling Hu, Mohammed Soutto, Abbes Belkhiri, Wael El-Rifai

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Esophageal adenocarcinoma (EAC) is a classic example of inflammation-associated cancer, which develops through GERD (gastro-esophageal reflux disease)-Barrett's esophagus (BE)-dysplasiaadenocarcinoma sequence. The incidence of EAC has been rising rapidly in the US 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 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 TNF-α-induced NF-κB transcriptional activity (P<.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, IL-6, IL-8, IL-1β, CXCL-1, and CXCL-2) following treatment with TNF-α in GPX7-expressing FLO-1 cells as compared to 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 TNFR1 and TRAF2, suggesting that GPX7 modulates critical upstream regulators of NFkB. We concluded that the loss of GPX7 expression is a critical step in promoting the TNF-α-induced activation of pro-inflammatory NF-κB signaling, a major player in GERD-associated Barrett's carcinogenesis.

Original languageEnglish (US)
Article numberbgu083
JournalCarcinogenesis
Volume35
Issue number7
DOIs
StatePublished - Jul 2014
Externally publishedYes

Keywords

  • Barrett's
  • Cancer
  • Cytokines
  • Glutathione peroxidase 7
  • Inflammation
  • NF-κB

ASJC Scopus subject areas

  • Cancer Research

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