Glutathione S-transferase-pi expression is downregulated in patients with Barrett's esophagus and esophageal adenocarcinoma.
The glutathione S-transferases (GSTs) are a family of enzymes that play an important role in the prevention of cancer by detoxifying numerous potentially carcinogenic compounds. GSTs conjugate reduced glutathione to a variety of electrophilic and hydrophobic compounds, converting them into more soluble, more easily excretable compounds. Decreased glutathione S-transferase-pi (GSTPI) enzyme activity has been reported in Barrett's esophagus, and an inverse correlation was demonstrated between GST enzyme activity and tumor incidence in the gastrointestinal tract, but the role of GSTPI messengerRNA (mRNA) expression in Barrett's esophagus and associated adenocarcinomas is uncertain. The purpose of this study was to investigate the role of GSTPI mRNA and protein expression in the development and progression of the Barrett's metaplasia-dysplasia-adenocarcinoma sequence, and to investigate the potential of GSTPI quantitation as a biomarker in the clinical management of this disease. GSTPI mRNA expression levels, in relation to the housekeeping gene beta-actin, were analyzed using a quantitative real-time reverse transcription-polymerase chain reaction method (TaqMan) in 111 specimens from 19 patients with Barrett's esophagus without carcinoma (BE group), 21 patients with Barrett's-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of Barrett's esophagus or chronic gastroesophageal reflux disease. GSTPI mRNA expression was detectable in all 111 samples investigated. Analyzed according to histopathologic group, the median GSTPI mRNA expression was highest in normal squamous esophagus epithelium, intermediate in Barrett's esophagus, and lowest in adenocarcinoma tissues (P < 0.001). The median GSTPI expression was significantly decreased in Barrett's esophagus tissues compared to matching normal squamous esophagus from either the BE group (P = 0.001) or the EA group (P = 0.023). GSTPI expression levels in adenocarcinoma tissues were decreased compared to matching normal esophagus tissues from the patients with adenocarcinoma (P = 0.011). Furthermore, GSTPI mRNA expression values were significantly different between metaplastic, dysplastic, and adenocarcinoma tissues (P = 0.026). GSTPI expression levels were also significantly lower in histologically normal squamous esophagus tissues from patients with cancer (EA group) compared to both normal esophagus tissues from patients without cancer (BE group; P = 0.007) and normal esophagus tissues from the control group with no esophageal abnormality (P = 0.002). GSTPI protein expression was generally highest in the basal layer of normal squamous esophagus epithelium and lowest in adenocarcinoma cells, with Barrett's cells showing intermediate staining intensity. Our results show that downregulation of GSTPI expression is an early event in the development of Barrett's esophagus and esophageal adenocarcinoma. Loss of GSTPI expression may have an important role in the development and progression of this disease.
Brabender
Jan
J
Department of Biochemistry, USC Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
Lord
Reginald V
RV
Wickramasinghe
Kumari
K
Metzger
Ralf
R
Schneider
Paul M
PM
Park
Ji-Min
JM
Hölscher
Arnulf H
AH
DeMeester
Tom R
TR
Danenberg
Kathleen D
KD
Danenberg
Peter V
PV
D000230:Adenocarcinoma / Q000201:enzymology*; D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000201:enzymology*; D018450:Disease Progression; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000201:enzymology*; D005260:Female; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction
D007527:Isoenzymes; D012333:RNA, Messenger; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase