Comparative proteomics analysis of chronic atrophic gastritis: changes of protein expression in chronic atrophic gastritis without Helicobacter pylori infection

Chronic atrophic gastritis (CAG) is a very common gastritis and one of the major precursor lesions of gastric cancer, one of the most common cancers worldwide. The molecular mechanism underlying CAG is unclear, but its elucidation is essential for the prevention and early detection of gastric cancer and appropriate intervention. A combination of two-dimensional gel electrophoresis and mass spectrometry was used in the present study to analyze the differentially expressed proteins. Samples from 21 patients (9 females and 12 males; mean age: 61.8 years) were used. We identified 18 differentially expressed proteins in CAG compared with matched normal mucosa. Eight proteins were up-regulated and 10 down-regulated in CAG when compared with the same amounts of proteins in individually matched normal gastric mucosa. Two novel proteins, proteasome activator subunit 1 (PSME1), which was down-regulated in CAG, and ribosomal protein S12 (RPS12), which was up-regulated in CAG, were further investigated. Their expression was validated by Western blot and RT-PCR in 15 CAG samples matched with normal mucosa. The expression level of RPS12 was significantly higher in CAG than in matched normal gastric mucosa (P < 0.05). In contrast, the expression level of PSME1 in CAG was significantly lower than in matched normal gastric mucosa (P < 0.05). This study clearly demonstrated that there are some changes in protein expression between CAG and normal mucosa. In these changes, down-regulation of PSME1 and up-regulation of RPS12 could be involved in the development of CAG. Thus, the differentially expressed proteins might play important roles in CAG as functional molecules.

Associations between a PTPN11 polymorphism and gastric atrophy--opposite in Uzbekistan to that in Japan.

Src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) of gastric epithelial cells interacts with cagA from Helicobacter pylori (H. pylori). Our previous studies found the AA genotype of a G/A single nucleotide polymorphism at intron 3 (rs2301756) of PTPN11 gene, which encodes SHP-2, to be associated with a lower risk of gastric atrophy. The present study aimed to examine the association with gastric atrophy among the subjects of a case-control study of peptic ulcer disease (PUD) conducted in the Uzbek Republic. Cases were 95 patients (61 males and 34 females) with PUD aged 16 to 85 years. Controls were 102 hospital volunteers (42 males and 60 females) including 42 patients with miscellaneous diseases, aged 15 to 75 years. Gastric atrophy was evaluated with serum pepsinogens (PG1<70 ng/ml and PG1/PG2<3). Polymorphisms of PTPN11 at intron 3 (rs2301756) and intron10 (rs12229892) were genotyped with PCR with confronting two-pair primers (PCR-CTPP). Anti-cagA IgG antibody was detected in 93.7% of cases and 77.5% in controls. Gastric atrophy was observed in 24.2% of the PUD patients and 33.3% in the controls. The A allele at intron 3 was completely linked to the G allele at intron 10. The age, sex, and group (cases and controls) adjusted odds ratio of gastric atrophy was 0.18 (95% confidence interval, 0.04-0.86) for intron 3 GG genotype relative to AA genotype. Since the finding was opposite to that among Japanese, the H. pylori strains and/or lifestyle in Uzbekistan might modify the association.

Gene Expression Profiling using Oligonucleotide Microarray in Atrophic Gastritis and Intestinal Metaplasia / 대한소화기학회지

BACKGROUND/AIMS: The atrophic gastritis with intestinal metaplasia of gastric mucosa has been considered to be the major factor of carcinogenesis in the stomach. However, the key molecules are still poorly understood. To elucidate the molecular genetic basis, we report the results of our initial microarray data to analyze the genome pattern in patients with atrophic gastritis and intestinal metaplasia of the stomach. METHODS: We used oligonucleotide microarray technique to evaluate the gene expression profiles in atrophic gastritis with intestinal metaplasia, in comparison with those of normal mucosa. For the identification of differentially expressed genes, Significance Analysis of Microarrays (SAM) package method was used. The results were analyzed using global normalization, intensity dependent normalization, and box plot normalization. RESULTS: Eight genes including FABP, REG, OR6C1, MEP1, SLC6A1, SI, Mucin 1, and RAB23 in mucosa of atrophic gastritis and intestinal metaplasia were up-regulated by more than 10 times as compared with normal gastric mucosa. Only one gene, LOC44119 was down-regulated by more than 10 times of the expression as compared with normal gastric mucosa. In respect to the expression of known genes related to gastric carcinogenesis, 8 genes including FN1, SRMS, TP53, TP53IMP2, TP53I3, FGFR4, TGFB1, and TGFA showed up- and down-regulations more than 2 folds in expression pattern. CONCLUSIONS: We could identify a total genome pattern in patient with atrophic gastritis and intestinal metaplasia using oligonucleotide microarray. We believe that the current results will serve as a fundamental bioinformative basis for clinical applications in diagnosis and treatment of gastric cancer and precancerous lesion in the future.

Microarray Analysis of Multiple Gene Expression in Intestinal Metaplasia and Atrophic Gastritis / 대한소화기학회지

No abstract availble.

The ACE gene polymorphism is associated with the incidence of gastric cancer among H. pylori seropositive subjects with atrophic gastritis.

Studies of the angiotensin converting enzyme (ACE) I/D polymorphism have provided evidence that the D/D genotype is associated with gastric tumor progression and numbers of lymph node metastases, but not with the overall risk of gastric cancer. The highest levels of circulating and tissue ACE activity were found in carriers of the D/D genotype. Here, we further investigated the association using 454 Japanese subjects undergoing a health checkup and 202 gastric cancer patients. The ACE polymorphism was not found to be linked with H. pylori seropositivity or gastric atrophy. However, among H. pylori seropositive subjects with atrophy, those with the I/D genotype had an increased risk of gastric cancer (OR=1.59; 95% CI, 1.02-2.48). We also established that the polymorphism did not lower the age at diagnosis of gastric cancer. Confirmation of the association between ACE polymorphisms and development of gastric cancer requires much larger studies, and the biological role also needs to be fully elucidated.

Alteraciones genéticas en gastritis crónica: Estudio de inestabilidad microsatelital y pérdida de la heterocigocidad / Genetic changes in chronic gastritis: study of microsatellite instability and loss of heterozygosity

Background: Multifocal chronic gastritis, associated to intestinal metaplasia, is considered a preneoplastic lesion, closely associated to intestinal type gastric cancer. Aim: To study the frequency of microsatellite instability (MSI) and loss of heterozygosity (LOH) in areas of chronic gastritis and intestinal metaplasia in gastric biopsies of patients without cancer. Material and methods: Gastric biopsy samples from 34 patients without cancer (22 with multifocal atrophic gastritis and 12 with diffuse antral gastritis), were studied. Glands from areas of chonic gastritis and intestinal metaplasia and lymphocytes, were collected using laser microdissection of paraffin embedded samples. The analysis of 15 mono and dinucleotide microsatellites was used to assess LOH and MSI. Results: LOH and MSI were found in some of the markers in 55% (12/22) and 59% (13/22) of cases with intestinal metaplasia, respectively. Only one of 12 areas with diffuse atrophic gastritis had MSI and a different area had LOH (p <0.05 or less, when compared with areas of multifocal atrophic gastritis). Three areas of normal epithelium in patients with multifocal atrophic gastritis, also had alterations. Most of these alterations were concordant with adjacent areas with intestinal metaplasia. Conclusions: LOH and MSI was found in areas of intestinal metaplasia in more than half of the studied cases and in few areas of atrophic gastritis without intestinal metaplasia. These findings suggest that genotypic alterations may precede phenotypic modifications and that intestinal metaplasia is a preneoplastic lesion (Rev Méd Chile 2003; 131: 1365-74).