Harry Hua-ng Xia

Apoptosis in gastric epithelium induced by Helicobacter pylori infection : Implications in gastric carcinogenesis

OBJECTIVES: Helicobacter pylori is an identified carcinogen for gastric cancer, however, the underlying mechanisms remain to be defined. In this review, we sought to elucidate the role of apoptosis in gastric carcinogenesis, to determine the influence of H. pylori infection on apoptosis, and finally to provide insights into the mechanisms by which H. pylori may lead to gastric carcinogenesis.METHODS:A broad-based MEDLINE and Current Contents literature search was performed to identify relevant publications between 1966 and March 2000 addressing H. pylori infection, apoptosis, cell proliferation, gastric carcinoma, oncogenes, and tumor suppressor genes, as well as the products of these genes. Abstracts from recent major conferences that provided adequate additional data were also included.RESULTS:Apoptotic cells are rare in the glandular neck region (the generative cell zone) of normal gastric mucosa. With progression of atrophic gastritis, the generative cell zone shifts downward and a relatively large number of apoptotic cells occur. In intestinalized glands, both apoptotic cells and proliferative cells are present in deeper portions of the glands, corresponding to the generative zone. A higher frequency of apoptosis has been observed in gastric dysplasia than in coexisting gastric carcinomas, whereas the number of proliferative cells is significantly higher in gastric carcinoma than in dysplasia. Upregulation of oncogene bcl-2 in premalignant lesions and “downregulation” of the gene after malignant change is probably a common event. Accumulation of p53 protein is first detected in dysplasia, although mutation of the p53 gene may occur in intestinal metaplasia. H. pylori infection induces apoptosis in gastric epithelial cells, which returns to normal after eradication of the infection. Numerous molecules produced by H. pylori including cytotoxin (VacA), lipopolysaccharide, monochloramine, and nitric oxide may directly induce apoptosis. Moreover, H. pylori–stimulated host inflammatory/immune responses lead to release of a large amount of cytokines. Cytokines produced by type 1 T helper cells, such as TNF-α and IFN-γ, markedly potentiate apoptosis. Gastric cell proliferation is significantly higher in patients with H. pylori infection than in normal controls, and eradication of the infection leads to a reduction in cell proliferation. Apoptosis and cell proliferation are also increased in precancerous lesions such as gastric atrophy, intestinal metaplasia, and dysplasia in the presence of H. pylori infection. However, H. pylori–induced apoptosis may no longer be cell cycle–dependent in these lesions because of the occurrence of alterations and mutations of apoptosis-regulating genes, resulting in a loss of balance between apoptosis and cell proliferation.CONCLUSIONS:It is hypothesized that H. pylori–induced apoptosis may play a key role in gastric carcinogenesis by increasing cell proliferation and/or resulting in gastric atrophy.

Helicobacter pylori infection is not associated with diabetes mellitus, nor with upper gastrointestinal symptoms in diabetes mellitus.

OBJECTIVE:The association between Helicobacter pylori (H. pylori) infection and diabetes mellitus is controversial. We aimed to determine the prevalence of H. pylori infection in patients with diabetes and nondiabetic controls, and assess whether H. pylori infection was associated with upper gastrointestinal (GI) symptoms in diabetes mellitus.METHODS:A total of 429 patients with type 1 (n = 49) or type 2 (n = 380) diabetes mellitus (48.6% women, mean age 60.7 yr) and 170 nondiabetic controls (34.7% women, mean age 60.4 yr) were evaluated. All subjects completed a validated questionnaire (the Diabetes Bowel Symptom Questionnaire) to determine upper GI symptoms, and a blood sample was tested for H. pylori infection using a validated ELISA kit (sensitivity 96%, specificity 94%).RESULTS:Seroprevalence of H. pylori was 33% and 32%, respectively, in patients with diabetes and controls (NS). In both groups, the seroprevalence was significantly higher in men than in women; 39% vs 25% (p = 0.002) in diabetic patients, and 40% vs 20% (p = 0.01) in controls. Patients with diabetes had a significantly higher prevalence of early satiety (OR = 2.30), fullness (OR = 3.15), and bloating (OR = 1.50) compared with controls. Upper GI symptoms were present in 49% of H. pylori-positive and 53% of H. pylori-negative patients with diabetes (OR = 0.87, 95% CI 0.58–1.31, p = 0.56). H. pylori infection was also not associated with any of the individual upper GI symptoms before or after adjustment for potential confounding factors. However, patient age and female gender were identified as independent risk factors for upper GI symptoms. Smoking was a risk factor for bloating and early satiety.CONCLUSIONS:H. pylori infection appears not to be associated with diabetes mellitus or upper GI symptoms in diabetes mellitus.

Antral-type mucosa in the gastric incisura, body, and fundus (antralization): a link between Helicobacter pylori infection and intestinal metaplasia?

OBJECTIVES:Helicobacter pylori is a carcinogen; gastric carcinoma involves a multistep process from chronic gastritis to atrophy, intestinal metaplasia, and dysplasia. The aims of this study were to determine the types of mucosa at different gastric sites in H. pylori-infected and uninfected patients, and whether the presence of antral-type mucosa in the incisura, body, and fundus is associated with gastric atrophy and intestinal metaplasia.METHODS:Two hundred and sixty-eight patients with dyspepsia were enrolled. Eight biopsies (i.e., antrum ×3, body ×2, fundus ×2, and incisura ×1) were obtained. One antral biopsy was used for the CLO-test. Three (each from the antrum, body, and fundus) were cultured. The remaining biopsies were examined histologically according to the updated Sydney System after staining with hematoxylin and eosin and Giemsa. A validated serological test was also applied.RESULTS:Overall, 113 (42%) patients were infected with H. pylori. At the incisura, antral-type mucosa was more prevalent in infected than in uninfected patients (84% vs 18%; odds ratio [OR] = 23.9, 95% confidence interval [CI] 12.5–45.8; p < 0.001). Atrophic gastritis and intestinal metaplasia at the incisura was present in 19.5% and 13.3%, respectively, of infected, and 4.5% and 3.2%, respectively, of uninfected patients (both p < 0.01). Moreover, atrophic gastritis at the incisura was associated with the presence of antral-type mucosa at the site (termed antralization); the prevalence of atrophic gastritis was 19.5% (24/123) in the presence of antralization, whereas the rate was 2.1% (3/145) without antralization (OR = 11.4, 95% CI 3.4–39.2; p < 0.001). Similarly, at the incisura, 16.3% (20/123) of “antralized” cases and 1.4% (2/145) of “unantralized” cases had intestinal metaplasia (OR = 13.8, 95% CI, 3.2–60.7; p < 0.001). The association between antralization at gastric body and fundus also appeared to be associated with atrophic gastritis and intestinal metaplasia at these sites.CONCLUSIONS:Atrophic gastritis and intestinal metaplasia occurs predominantly at the gastric antrum and incisura with H. pylori infection. Antralization of the gastric incisura is a common event in H. pylori-infected patients, and appears to be associated with an increased risk of atrophic gastritis and intestinal metaplasia.

DISTRIBUTION OF DISTINCT VACA, CAGA AND ICEA ALLELES IN HELICOBACTER PYLORI IN HONG KONG

There is a substantial genetic heterogeneity among Helicobacter pylori strains, and certain genotypes have been suggested to be associated with the virulence of this pathogen. The aim of this study was to investigate the distribution of H. pylori vacA, cagA and iceA genotypes and their association with duodenal ulcer disease in Hong Kong.

Association between interleukin-1 gene polymorphisms and Helicobacter pylori infection in gastric carcinogenesis in a Chinese population

Background and Aim:  Helicobacter pylori is a major cause of chronic gastritis and peptic ulcer disease and a definite carcinogen for gastric adenocarcinoma. However, the underlying pathogenic mechanisms are not fully understood. Interleukin‐1 (IL‐1) is a key cytokine involved in H. pylori‐induced gastric inflammation. The present study aimed to determine polymorphisms of IL‐1B and IL‐1 receptor antagonist (IL‐1RN) genes and their association with H. pylori infection and gastroduodenal diseases in Chinese patients.

HSF1 Down-regulates XAF1 through Transcriptional Regulation

Studies have indicated the role of HSF1 (heat-shock transcription factor 1) in repressing the transcription of some nonheat shock genes. XAF1 (XIAP-associated factor 1) was an inhibitor of apoptosis-interacting protein with the effect of antagonizing the cytoprotective role of XIAP. XAF1 expression was lower in gastrointestinal cancers than in normal tissues with the mechanism unclear. Here we showed that gastrointestinal cancer tissues expressed higher levels of HSF1 than matched normal tissues. The expression of XAF1 and HSF1 was negatively correlated in gastrointestinal cancer cell lines. Stress stimuli, including heat, hypo-osmolarity, and H2O2, significantly suppressed the expression of XAF1, whereas the alteration of HSF1 expression negatively correlated with XAF1 expression. We cloned varying lengths of the 5′-flanking region of the XAF1 gene into luciferase reporter vectors, and we evaluated their promoter activities. A transcription silencer was found between the –592- and –1414-nucleotide region that was rich in nGAAn/nT-TCn elements (where n indicates G, A, T, or C). A high affinity and functional HSF1-binding element within the –862/–821-nucleotide region was determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Inactivation of this “heat-shock element” by either site-directed mutation or an HSF1 inhibitor, pifithrin-α, restored the promoter activity of the silencer structure. Moreover, pretreatment with antioxidants suppressed HSF1 binding activity and increased the transcriptional activity and expression of XAF1. These findings suggested that endogenous stress pressure in cancer cells sustained the high level expression of HSF1 and subsequently suppressed XAF1 expression, implicating the synergized effect of two anti-apoptotic protein families, HSP and inhibitors of apoptosis, in cytoprotection under stress circumstances.

Alternative and rescue treatment regimens for Helicobacter pylori eradication

Eradication therapy has been incorporated into clinical practice. The regimens currently recommended for first-line treatment include a 2-week bismuth-based triple therapy (mainly in developing countries), a 1 – 2 week proton pump inhibitor (PPI)-based triple therapy and a 1-week ranitidine bismuth citrate (RBC)-based triple therapy. However, these regimens fail to eradicate Helicobacter pylori in up to 20% of patients due to poor compliance, inadequate treatment duration, smoking, old age and bacterial resistance to nitroimidazoles and/or macrolides in particular. Therefore, alternative regimens that avoid nitroimidazoles and/or macrolides or overcome bacterial resistance to these drugs, improve compliance, minimise side effects and/or reduce costs have been evaluated. One-week quadruple therapy, which adds a PPI or histamine receptor 2-blocker to bismuth-based triple therapy, usually achieves an eradication rate of 90% when used as an alternative first-line therapy but the efficacy decreases when used as a rescue therapy. Several new triple therapies that may be used as alternative and/or rescue therapies have been evaluated. Among these are furazolidone-based (furazolidone plus an antibiotic and a bismuth salt, a PPI or RBC), fluoroquinolone-based (levofloxacin or moxifloxacin plus an antibiotic and a PPI) and ecabet sodium-based (ecabet plus two antibiotics) triple therapies. Recently, rifabutin has been used in combination with a PPI and amoxycillin as a rescue therapy, with satisfactory eradication rates. In addition, a number of new antimicrobial agents are currently under investigation in in vitro studies but the clinical values of these agents needs to be confirmed.

Reduction of Peptic Ulcer Disease and Helicobacter pylori Infection but Increase of Reflux Esophagitis in Western Sydney Between 1990 and 1998

We aimed to determine if changes in the patterns of upper gastrointestinal diseases at endoscopy have occurred over the past decade. Retrospectively, 917 consecutive patients were selected based on upper endoscopy between June 1 and August 31, in 1990 (n = 217), 1994 (n = 270), and 1998 (n = 430). Demographic, clinical, endoscopic, and histological information were extracted from the medical records on a standardized case record form. Over the eight-year period, follow-up of peptic ulcer (15%, 5%, and 5%, respectively, in 1990, 1994, and 1998, df = 2, P < 0.001), bleeding (22%, 14%, and 13%, P = 0.008), and nausea/vomiting (15%, 16%, and 10%, df = 2, P = 0.003) had become less frequent, but reflux (21%, 19%, and 34%, df = 2, P < 0.001) and dyspepsia (24%, 43%, and 32%, df = 2, P < 0.001) more frequent indications for upper endoscopy. The prevalence of peptic ulcer disease decreased (22%, 15%, and 13%, df = 2, P = 0.025), but the prevalence of reflux esophagitis increased significantly (29%, 30%, and 39%, df = 2, P = 0.010). The prevalence of both the use of nonsteroidal antiinflammatory drugs (NSAIDs) (18%, 20%, and 11%, respectively, in 1990, 1994, and 1998, df = 2, P = 0.004) and H. pylori infection (39% in 1994 and 30% in 1998, df = 1, P = 0.032) decreased. Overall, NSAID use was independently associated with gastric ulcers (OR = 2.39, 95% CI 1.21–4.73, χ2 = 6.31, df = 1, P = 0.012), but not esophagitis. H. pylori infection was independently associated with duodenal ulcers (OR = 4.74, 95% CI 2.30–9.77, χ2 = 17.8, df = 1, P < 0.001), histologically chronic (OR = 166.8, 95% CI 76.1–365.4, χ2 = 313.0, df = 1, P < 0.001) and active (OR = 30.1, 95% CI 17.0–53.5, χ2 = 189.7, df = 1, P < 0.001) gastritis and lymphoid aggregates (OR = 5.49, 95% CI 3.02–9.97, χ2 = 36.3, df = 1, P < 0.001). In conclusion, the prevalence of peptic ulcer disease appears to have been decreasing, whereas reflux esophagitis has been increasing over the past decade in Western Sydney. The decreased use of NSAIDs and decline of H. pylori infection have likely both contributed to the reduction of peptic ulcer disease, but the increase in reflux esophagitis remains to be fully explained.

TNF Gene Polymorphisms and Helicobacter Pylori Infection in Gastric Carcinogenesis in Chinese Population

BACKGROUND AND AIMS:Helicobacter pylori (H. pylori) is a major cause of chronic gastritis and peptic ulcer disease, and a definite carcinogen for gastric adenocarcinoma. However, the underlying pathogenic mechanisms have not been fully understood although the interactions between environmental, bacterial, and multiple genetic components are likely to be involved. Tumor necrosis factor (TNF) is a key cytokine involved in H. pylori-induced gastric inflammation. The present study aimed to determine the di-allelic polymorphisms of TNF gene and their association with H. pylori infection and gastroduodenal diseases in Chinese population of Han nationality.METHODS:Two hundred and ten patients with gastroduodenal diseases (73 chronic gastritis, 78 duodenal ulcer, and 59 noncardia gastric cancer) and 264 healthy controls were genotyped by the PCR-RFLP method for TNF-α 308, lymphotoxin-α (LT-α) NcoI, and AspHI gene polymorphisms. H. pylori infection status was determined by a validated serological test.RESULTS:H. pylori infection was detected in 90.5% of 210 patients and 62.1% of 264 healthy controls (p < 0.0001; odds ratio [OR]= 5.793; 95%CI: 3.431–9.780). Frequency of LT-αNcoI A/G genotype in patients with noncardia gastric cancer with H. pylori infection was significantly higher than that in H. pylori-positive healthy controls (64.0%vs 46.0%; p = 0.0297; OR = 2.026; 95%CI: 1.080–3.803). There were no other associations between TNF-α 308, LT-αNcoI, and AspHI gene polymorphisms and H. pylori infection in gastroduodenal diseases.CONCLUSIONS:LT-αNcoI A/G heterozygous genotype was associated with H. pylori infection in patients with noncardia gastric cancer in Chinese Han population.

Serum macrophage migration‐inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer

This study aimed to determine the potential diagnostic value of migration‐inhibitory factor (MIF) for gastric cancer in patients presenting with dyspepsia and its prognostic value for gastric cancer.