J Cancer 2014; 5(7):510-517. doi:10.7150/jca.9215 This issue

Research Paper

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

Dun-Fa Peng1, Tian-Ling Hu1,3, Mohammed Soutto1,3, Abbes Belkhiri1, Wael El-Rifai1,2,3✉

1. Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA;
2. Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA;
3. Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, TN, USA.

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Peng DF, Hu TL, Soutto M, Belkhiri A, El-Rifai W. Glutathione Peroxidase 7 Suppresses Bile Salt-Induced Expression of Pro-Inflammatory Cytokines in Barrett's Carcinogenesis. J Cancer 2014; 5(7):510-517. doi:10.7150/jca.9215. Available from https://www.jcancer.org/v05p0510.htm

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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-α, IL-1β, 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-κB-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-α, IL-1β 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.

Keywords: glutathione, inflammation, cytokine, reflux, GERD, bile salts, Barrett's, cancer, esophagus, NF-κB.