Glutathione peroxidase isoforms as part of the local antioxidative defense system in normal and Barrett's esophagus

Abstract

The development of an oesophageal adenocarcinoma arising in Barrett's mucosa is associated with a multistep process of genetic lesions that may be triggered by persistent oxidative damage. The glutathione peroxidase isoforms pGPx and GI-GPx, which were identified recently in the mucosa of the esophagus, may play a role as defense factors to prevent such oxidative injury. To determine alterations of the expression of pGPx and GI-GPx in Barrett's mucosa as compared to primary and regenerative squamous epithelium. Biopsy samples of oesophageal mucosa of patients with Barrett's esophagus (n ‫؍‬ 12), patients with squamous restoration after thermal ablation (n ‫؍‬ 10), and healthy controls (n ‫؍‬ 5) were analyzed for pGPx and GI-GPx mRNA expression by Northern blot and for glutathione peroxidase activity by enzymatic assay. Squamous regeneration was induced by argon plasma coagulation (APC) combined with proton pump inhibitor therapy. In Barrett's epithelium mRNA levels of pGPx (the secreted isoform) were significantly reduced and of GI-GPx (the intracellular isoform) significantly increased as compared to normal squamous mucosa. In squamous mucosa that had regenerated after APC, no significant differences compared to the expression pattern of primary squamous mucosa were found. Compared to squamous mucosa, Barrett's metaplasia shows a different mRNA expression of pGPx and GI-GPx that may be associated with increased susceptibility to oxidative damage.

Gpx2 Is an Overexpressed Gene in Rat Breast Cancers Induced by Three Different Chemical Carcinogens

“…There have already been a few reports showing an involvement of Gpx2 in cancer: mice with target disruption of Gpx2 together with Gpx1 have been associated with inflammation-induced cancer formation; the expression of Gpx2 was shown to be reduced in the epithelium of prostatic intraepithelial neoplasia in Nkx3.1 mutant mice; and overexpression of GPX2 has been found in human colorectal adenomas, Barrett's mucosa of the esophagus, and rat hepatocarcinogenesis (13)(14)(15)(16)(17)(18). In addition, inactivation of GPX2 has been associated with UV-induced squamous cell carcinoma of skin (19), and in the public data base Gene Expressing Omnibus (GEO), a similar result to our present data, which shows that Gpx2 is overexpressed in MNU-induced breast cancers of Wistar-Furth female rats, is deposited (GDS1363).…”

Glutathione Peroxidase 2 Inhibits Cyclooxygenase-2–Mediated Migration and Invasion of HT-29 Adenocarcinoma Cells but Supports Their Growth as Tumors in Nude Mice

“…The gastrointestinal GPx2 is not uniformly expressed in the intestine but is highest in the crypt grounds and decreases gradually toward the luminal surface (14), indicating a role in proliferating cells. GPx2 expression is increased in human colorectal adenomas (14), carcinomas (15), and in Barrett's esophageal mucosa (16). GPx2 expression, however, is not specific for the gastrointestinal tract.…”

The GI-GPx Gene Is a Target for Nrf2

“…In the small intestine, its concentration is especially high in Paneth cells (25), which play a major role in mucosal immunity: e.g., by secreting microbicidal defensins upon exposure to bacteria (2). (iv) GI-GPx is up-regulated in human colorectal adenomas (25,39,43), in Barrett's esophageal mucosa (44), and during neoplastic transformation of squamous epithelial cells (55). (v) While a single knockout (KO) of cGPx remains largely asymptomatic (31), a double KO of GPx1 and GPx2 (GPx1/2 KO) results in inflammatory bowel disease and increased intestinal cancer incidence (14), making a role for GI-GPx in preventing carcinogenesis likely.…”