Loss of glutathione peroxidase 7 promotes TNF-?-induced NF-?B 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-?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.

SUBMITTER: Peng DF 

PROVIDER: S-EPMC4076814 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other