Inducible nitric oxide synthase, nitrotyrosine and p53 mutations in the molecular pathogenesis of Barrett's esophagus and esophageal adenocarcinoma.
Nitric oxide (NO) has been implicated as a potential causative factor for endogenous p53 mutations in gastrointestinal malignancy. To investigate the role of NO in esophageal adenocarcinoma (EADC), we studied patterns of p53 mutations, expression of inducible nitric oxide synthase (iNOS) and the tissue accumulation of nitrotyrosine (NTS), a stable reaction product of NO and a marker for cellular protein damage, in human premalignant and malignant esophageal epithelia. Tissues were obtained from patients with gastroesophageal reflux disease (GERD)-induced esophagitis (n = 76), Barrett's esophagus (BE; n = 119) and primary EADC (n = 54). DNA sequencing was used to characterize p53 mutations, RT-PCR to study iNOS mRNA expression, and immunohistochemistry to study NTS. Relative to self-matched normal epithelia, a progressive increase in iNOS mRNA expression was seen in GERD (30%; 23/76), BE (48%; 57/119), and EADC (63%; 34/54) tissues (P < 0.001). Among patients with EADC, elevated levels of NTS immunoreactivity were more frequent in tumors with p53 mutations (11/21; 52%) compared with tumors with wild-type p53 (9/33; 27%; P = 0.063), and specifically in tumors with p53 mutations at CpG dinucleotides (10/12; 83%) compared with non-CpG p53 mutations (1/9; 11%; P = 0.008). The increasing frequency of iNOS (mRNA) overexpression in GERD, BE and EADC supports the hypothesis that an active inflammatory process, most likely a consequence of GERD, underlies molecular progression to EADC. The highly significant association between NTS, reflecting chronic NO-induced cellular protein damage, and endogenous p53 mutations at CpG dinucleotides, provides further evidence for a molecular link between chronic inflammation and esophageal malignancy.
Vaninetti
Nadine M
NM
Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Geldenhuys
Laurette
L
Porter
Geoffrey A
GA
Risch
Harvey
H
Hainaut
Pierre
P
Guernsey
Duane L
DL
Casson
Alan G
AG
D000230:Adenocarcinoma / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002908:Chronic Disease; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D005260:Female; D016158:Genes, p53; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D017354:Point Mutation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000502:physiology
D018836:Inflammation Mediators; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II