Cellular stress and redox activity proteins are involved in gastric carcinogenesis associated with Helicobacter pylori infection expressing high levels of thioredoxin-1 / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Helicobacter pylori infection is related to the development of gastric diseases. Our previous studies showed that high thioredoxin-1 (Trx1) expression in H. pylori can promote gastric carcinogenesis. To explore the underlying molecular mechanisms, we performed an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic analysis of stomach tissues from Mongolian gerbil infected with H. pylori expressing high and low Trx1. Differences in the profiles of the expressed proteins were analyzed by bioinformatics and verified using Western blot analysis. We found three candidate proteins, 14-3-3α/β, glutathione-S-transferase (GST), and heat shock protein 70 (HSP70), in high Trx1 tissues compared with low Trx1 tissues and concluded that cellular stress and redox activity-related proteins were involved in the pathogenesis of gastric cancer associated with H. pylori Trx1.

Helicobacter pylori Eradication Downregulates Cellular Inhibitor of Apoptosis Protein 2 in Gastric Carcinogenesis

BACKGROUND/AIMS: To evaluate the expression of cellular inhibitor of apoptosis protein 2 (cIAP2) during gastric carcinogenesis after Helicobacter pylori (HP) infection and after HP eradication. METHODS: We divided non-cancer patients into four groups according to the status of HP infection and atrophic gastritis (AG)/intestinal metaplasia (IM). We compared cIAP2 mRNA expression among these four groups and patients with HP-positive early gastric cancer (EGC) by using real-time polymerase chain reaction (PCR). We evaluated the expression of cIAP2 messenger RNA (mRNA)/protein by using real-time PCR/immunohistochemistry and the degree of apoptosis with a terminal deoxynucleotidyl transferase-mediated nick end labeling assay before and 12 months after endoscopic submucosal dissection (ESD) in HP-positive EGC patients, regardless of whether they had undergone eradication therapy. RESULTS: The expression of cIAP2 mRNA was significantly higher in the groups with HP(+), AG/IM(+), and HP-positive EGC than in the control, HP(+), and AG/IM(−) groups (p<0.005). In the HP eradication group, the expression of cIAP2 mRNA/protein significantly decreased (p=0.006) and apoptosis increased at the 12-month follow-up after ESD. In the HP noneradication group, the aforementioned changes were not found during the same follow-up period. CONCLUSIONS: The expression of cIAP2 increased during gastric carcinogenesis after HP infection; HP eradication in the patients who had undergone ESD for EGC reversed overexpression of cIAP2 and suppressed cell apoptosis.

Gastric Carcinogenesis in the miR-222/221 Transgenic Mouse Model / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: MicroRNAs (miRNAs) regulate various cellular functions, including development, cell proliferation, apoptosis, and tumorigenesis. Different signatures associated with various tissue types, diagnosis, progression, prognosis, staging, and treatment response have been identified by miRNA expression profiling of human tumors. miRNAs function as oncogenes or as tumor suppressors. The relationship between gastric cancer and miRNA garnered attention due to the high incidence of gastric cancer in Asian countries. miR-222/221 expression increases in gastric tumor tissues. The oncogenic effect of miR-222/221 was previously determined in functional studies and xenograft models. In this study, transgenic mice over-expressing miR-222/221 were generated to confirm the effect of miR-222/221 on gastric carcinogenesis. MATERIALS AND METHODS: At 6 weeks of age, 65 transgenic mice and 53 wild-type mice were given drinking water containing N-nitroso-N-methylurea (MNU) for 5 alternating weeks to induce gastric cancer. The mice were euthanized at 36 weeks of age and histologic analysis was performed. RESULTS: Hyperplasia was observed in 3.77% of the wild-type mice and in 18.46% of the transgenic mice (p=0.020). Adenoma was observed in 20.75% of the wild-type mice and 26.15% of the transgenic mice (p=0.522). Carcinoma was observed in 32.08% of the wild-type mice and 41.54% of the transgenic mice (p=0.341). The frequency of hyperplasia, adenoma, and carcinoma was higher in transgenic mice, but the difference was statistically significant only in hyperplasia. CONCLUSION: These results suggest that hyperplasia, a gastric pre-cancerous lesion, is associated with miR-222/221 expression but miR-222/221 expression does not affect tumorigenesis itself.

Anticancer Effect of Lycopene in Gastric Carcinogenesis

Gastric cancer ranks as the most common cancer and the second leading cause of cancer-related death in the world. Risk factors of gastric carcinogenesis include oxidative stress, DNA damage, Helicobacter pylori infection, bad eating habits, and smoking. Since oxidative stress is related to DNA damage, smoking, and H. pylori infection, scavenging of reactive oxygen species may be beneficial for prevention of gastric carcinogenesis. Lycopene, one of the naturally occurring carotenoids, has unique structural and chemical features that contributes to a potent antioxidant activity. It shows a potential anticancer activity and reduces gastric cancer incidence. This review will summarize anticancer effect and mechanism of lycopene on gastric carcinogenesis based on the recent experimental and clinical studies.

Study on inhibition of Dendrobium officinale extract on gastric carcinogenesis / 中草药

Objective: To explore the inhibitory effects of Dendrobium officinale extract (DOE) on gastric carcinogenesis and its related molecular mechanism. Methods: The rats were randomly divided into normal group, model group, positive drug group, low-dose and high-dose DOE groups. The gastric carcinogenesis model was induced by ig giving 200 mg/kg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at doses of 200 mg/kg every 10 days for 3 months. Meanwhile, the rats in the treatment groups were given the corresponding doses of drug while the rats in the control group were given normal saline. At the end of the experiment, the degree of gastric tissue carcinogenesis was calculated by HE staining analysis. The expression levels of EGF, EGFR, Bax, and Bcl-2 mRNA were detected by RT-PCR test in gastric tissue. The levels of EGF and EGFR in plasma were detected by ELISA. Apoptosis was detected by TUNEL assay. Results: Compared with the model group, the high-dose DOE could inhibit the degree of carcinogenesis significantly (P < 0.01). Both high-dose and low-dose DOE could significantly reduce the levels of EGF, EGFR mRNA, and Bcl-2 mRNA, and increase the levels of Bax mRNA in gastric tissue, with statistical significance compared with the model group (P < 0.05, 0.01). In addition, they also reduced the levels of EGF and EGFR in plasma significantly and induced apoptosis. Conclusion: DOE could inhibit the gastric carcinogenesis, which might be related to effects of decreasing the expression of EGF and EGFR mRNA in gastric tissue and EGF and EGFR in plasma and inducing the apoptosis through reducing the expression of Bcl-2 mRNA and increasing Bax mRNA.

Different MicroRNA Expression Levels in Gastric Cancer Depending on Helicobacter pylori Infection

BACKGROUND/AIMS: This study was conducted to identify microRNAs (miRNAs) that are differentially expressed in Helicobacter pylori-infected patients with an intestinal type of gastric cancer using miRNA microarray and to confirm the candidate miRNA expression levels. METHODS: Total RNA was extracted from the cancerous and noncancerous regions of formalin-fixed, paraffin-embedded tissues of H. pylori-positive (n=8) or H. pylori-negative (n=8) patients with an intestinal type of gastric cancer. RNA expression was analyzed using a 3,523 miRNA profiling microarray based on the Sanger miRBase. Validation analysis was performed using TaqMan miRNA assays. RESULTS: A total of 219 miRNAs in the aberrant miRNA profiles across the miRNA microarray showed at least a 2-fold change differential expression in H. pylori-positive and H. pylori-negative cancer tissues. After candidate miRNAs were selected using online miRNA databases, TaqMan miRNA assays confirmed that three miRNAs (miR-99b-3p, miR-564, and miR-638) were significantly increased in three H. pylori-positive cancer tissues compared to the H. pylori-negative cancer tissues. Additionally, four miRNAs (miR-204-5p, miR-338-5p, miR-375, and miR-548c-3p) were significantly increased in H. pylori-negative cancer tissues compared to H. pylori-positive cancer tissues. CONCLUSIONS: miRNA expression in the intestinal type of H. pylori infection-dependent gastric cancer suggests that different gastric cancer pathogenesis mechanisms could exist between H. pylori-positive and H. pylori-negative gastric cancer. Additional functional studies are required.

Different MicroRNA Expression Levels in Gastric Cancer Depending on Helicobacter pylori Infection

BACKGROUND/AIMS: This study was conducted to identify microRNAs (miRNAs) that are differentially expressed in Helicobacter pylori-infected patients with an intestinal type of gastric cancer using miRNA microarray and to confirm the candidate miRNA expression levels. METHODS: Total RNA was extracted from the cancerous and noncancerous regions of formalin-fixed, paraffin-embedded tissues of H. pylori-positive (n=8) or H. pylori-negative (n=8) patients with an intestinal type of gastric cancer. RNA expression was analyzed using a 3,523 miRNA profiling microarray based on the Sanger miRBase. Validation analysis was performed using TaqMan miRNA assays. RESULTS: A total of 219 miRNAs in the aberrant miRNA profiles across the miRNA microarray showed at least a 2-fold change differential expression in H. pylori-positive and H. pylori-negative cancer tissues. After candidate miRNAs were selected using online miRNA databases, TaqMan miRNA assays confirmed that three miRNAs (miR-99b-3p, miR-564, and miR-638) were significantly increased in three H. pylori-positive cancer tissues compared to the H. pylori-negative cancer tissues. Additionally, four miRNAs (miR-204-5p, miR-338-5p, miR-375, and miR-548c-3p) were significantly increased in H. pylori-negative cancer tissues compared to H. pylori-positive cancer tissues. CONCLUSIONS: miRNA expression in the intestinal type of H. pylori infection-dependent gastric cancer suggests that different gastric cancer pathogenesis mechanisms could exist between H. pylori-positive and H. pylori-negative gastric cancer. Additional functional studies are required.

Evolutionary History of the Helicobacter pylori Genome: Implications for Gastric Carcinogenesis

The genome of the bacterium Helicobacter pylori has evolved over the millennia since its migration out of Africa along with its human host approximately 60,000 years ago. Human migrations, after thousands of years of permanent settlement in those lands, resulted in seven prototypes of genetic populations of H. pylori with distinct geographical distributions. In all continents, present day isolates of H. pylori have molecular markers that reflect population migrations. The colonization of the Americas as well as the slave trade introduced European and African strains to the New World. The relationship between H. pylori genome and gastric cancer rates is linked to the presence of the cagA gene, but the knowledge on this subject is incomplete because other genes may be involved in certain populations. A new situation for Homo sapiens is the absence of H. pylori colonization in certain, mostly affluent, populations, apparently brought about by improved home sanitation and widespread use of antibiotics during the last decades. The disappearance of H. pylori from the human microbiota may be linked to emerging epidemics of esophageal adenocarcinoma, some allergic diseases such as asthma and some autoimmune disorders.

The enigma of Helicobacter pylori infection and gastric cancer.

Abstract Although H. pylori has been recognized as a class I carcinogen, incongruence between infection prevalence and cancer incidence has been reported. Holcombe called attention to the high prevalence of infection in the face of low cancer rates, which he called “The African Enigma”. Similar observations have now been made in other geographic areas. Gastric carcinoma should be considered an infectious disease, for which the classical epidemiologic model of causality applies. The model proposes that tissue injury inflicted by the infectious agent is modulated by its interactions with host and environmental factors. Although approximately half of the world’s population is infected, only a small proportion of people develop cancer. The African enigma is a striking example of the major contrasts in cancer risk among populations with similarly high prevalence of infection. The mechanisms involved in reducing the risk of cancer in infected individuals are explored in this article, which may lead to the design of effective prevention strategies.

Perspective of Helicobacter pylori Research: Molecular Pathogenesis of Helicobacter pylori Virulence Factors / 대한소화기학회지

Helicobacter pylori (H. pylori) causes chronic gastritis in human stomach, a minority of which progress to peptic ulcer disease, atrophic gastritis, or gastric malignancies. Clinical outcomes of H. pylori infection has been shown to depend on the variability of H. pylori virulence factors, host susceptibility, environmental factors and their interactions. This review provides an update on the molecular pathogenesis of H. pylori infection, focused on H. pylori virulence factors, H. pylori-gastric epithelium interactions, and modulation of host cell signaling. Understanding of H. pylori molecular pathogenic mechanism will facilitate the development of novel treatment strategies for eradication of the bacterium and prevention of H. pylori-induced gastropathy.

A study on the epithelial proliferation in Helicobacter pylori associated gastric premalignant and malignant lesions / 대한내과학회지

BACKGROUND: Many studies have demonstrated that increased cell proliferation in gastric epithelium is associated with Helicobacter pylori (H. pylori) infection. Increased epithelial proliferation is one of the earliest mucosal changes observed in gastric carcinogenesis. The aim of this study was to evaluate the influence of H. pylori infection for epithelial proliferation at different stages of gastric carcinogenesis from chronic gastritis to adenocarcinoma. METHODS: Gastric biopsy specimens were collected from 129 patients who underwent esophagogastroduodenoscopy with biopsy. Histologically, there were 29 patients with chronic gastritis, 26 chronic gastritis with intestinal metaplasia, 31 low grade dysplasia, 18 high grade dysplasia, and 25 gastric adenocarcinoma. Status of H. pylori infection was determined by rapid urease test, modified Giemsa stain and 13C-urea breath test. Epithelial cell proliferation was assessed by immunohistochemical method using anti-PCNA antibody. RESULTS: The grade of epithelial proliferation was higher in H. pylori infected patients than uninfected patients (p=0.007) and progressively increased at different stages from chronic gastritis to gastric adenocarcinoma (p<0.001). The analysis of epithelial proliferation according to H. pylori infection status in each histologic group showed that the grades of epithelial proliferation were higher in H. pylori infected patients than uninfected patients in all groups except adenocarcinoma group. CONCLUSION: H. pylori infection causes increased gastric epithelial cell proliferation and may play an important role in gastric carcinogenesis.