Notch1 directly induced CD133 expression in human diffuse type gastric cancers.

CD133 is considered as a stem-like cell marker in some cancers including gastric cancers, and Notch1 signaling is known to play an important role in the maintenance and differentiation of stem-like cells. We aimed to investigate whether Notch1 signaling contributes to the carcinogenesis of gastric cancers and CD133 induction. CD133 expression was detected in 51.4% of diffuse type gastric cancers while it was not detected in intestinal type gastric cancers. Similarly, only poorly-differentiated gastric cancer cell lines expressed CD133 and activated-Notch1. Inhibiting Notch1 signaling resulted in decreased CD133 expression, side population cells, cell proliferation and anchorage independent cell growth. Chromatin immunoprecipitation suggested that this Notch1 dependent regulation of CD133 was caused by direct binding of activated-Notch1 to the RBP-Jκ binding site in the 5' promoter region of CD133 gene. In addition, knocking down RBP-Jκ reduced CD133 induction in activated-Notch1 transfected cells. These findings suggested that Notch1 signaling plays an important role in the maintenance of the cancer stem-like phenotype in diffuse type gastric cancer through an RBP-Jκ dependent pathway and that inhibiting Notch1 signaling could be an effective therapy against CD133 positive diffuse type gastric cancers.

Accommodation in a refugee shelter as a risk factor for peptic ulcer bleeding after the Great East Japan Earthquake: a case-control study of 329 patients.

BACKGROUND: We have reported that the total number of peptic ulcers (PUs) had increased 1.5-fold after the Great East Japan Earthquake compared with those of the previous year, and that hemorrhagic ulcers were more prominently increased by 2.2-fold. The aim of this study is to determine the risk factors for bleeding ulcers after the Great East Japan Earthquake. METHODS: Clinical data of all peptic ulcer subjects endoscopically detected at the 7 major hospitals in the middle of the stricken area during the 3 months after the earthquake were retrospectively collected. Based on endoscopic and laboratory findings, peptic ulcer cases were divided into 227 bleeding ulcer cases and 102 non-bleeding controls. Other than ordinary risk factors for bleeding ulcers, the refugee shelter was included in the analysis as a unique confounder after the earthquake. Multiple logistic regression analyses were used to adjust for potential confounders. RESULTS: Eighty-seven (27%) of 329 PUs emerged from refuge shelters, and the majority (76 of 87) of PUs occurring in such shelters was the bleeding type. Multivariate regression showed that residence in a shelter was a strong risk factor for ulcer bleeding with OR (95% CI): 4.4 (2.1-9.6, p < 0.0001), independent of the progressiveness of ulcer diseases. CONCLUSIONS: Accommodation in a refugee shelter can be a strong risk factor for ulcer bleeding after a large-scale disaster. Since acid-suppressive drugs are supposed to decrease the risk for stress-induced ulcer bleeding, our results will encourage effective use of a limited medical resource in such catastrophic events.

Hemorrhagic ulcers after Great East Japan Earthquake and Tsunami: features of post-disaster hemorrhagic ulcers.

BACKGROUND: We investigated the characteristic features and treatment of hemorrhagic peptic ulcers after the Great East Japan Earthquake, which occurred on 11 March 2011. METHODS: Clinical data of patients with hemorrhagic peptic ulcers were retrospectively collected during the 3 months after the earthquake from seven major hospitals in the middle of the stricken area, and were compared with those during the same period of the previous year. RESULTS: After the earthquake, the number of hemorrhagic ulcers increased 2.2 fold as compared with the previous year, and gastric ulcers were significantly more frequent compared with duodenal ulcers (p < 0.05) and more often presented multiple forms (p < 0.05). Nonetheless, the proportion of re-bleeding cases after hemostasis treatment (8% in 2010 vs. 5% in 2011) or total mortality rate (2.5% in 2010 vs. 1.2% in 2011) was rather lower after the earthquake compared with that of the previous year. CONCLUSION: We clarified that post-disaster hemorrhagic ulcers existed frequently in the stomach, often as multiple ulcers at the same time. The Great East Japan Earthquake and Tsunami caused many cases of hemorrhagic ulcer. However, because of the high success rate of endoscopic hemostasis, the mortality remained as low as in the previous year. Our present study provides important information for large-scale disasters which can occur anywhere.

Peptic ulcers after the Great East Japan earthquake and tsunami: possible existence of psychosocial stress ulcers in humans.

BACKGROUND: Societal stress derived from an event that affects the whole society, e. g., a natural disaster, provides a unique, indirect way of determining the relationship between psychological stress and peptic ulcer disease in humans. In this study, we investigated the changing patterns of the incidence of peptic ulcers before and after the Great East Japan earthquake, which occurred on 11 March, 2011. METHODS: Clinical data of patients with peptic ulcers were retrospectively collected during the 3 months after the earthquake (2011) from 7 major hospitals in the middle of the stricken area, and were compared with the data for the same period of the previous year (2010). The eligible subjects were classified into four groups according to Helicobacter pylori infection status and intake of nonsteroidal anti-inflammatory drugs (NSAIDs). RESULTS: The incidence of all types of peptic ulcers was 1.5-fold increased after the earthquake, and in particular, the incidence of hemorrhagic ulcers was 2.2-fold increased; the gastric ulcer/duodenal ulcer ratio in hemorrhagic ulcers was also significantly increased (p < 0.05). Regarding the etiology of the peptic ulcers, the proportion of non-H. pylori and non-NSAID ulcers was significantly increased, from 13 % in 2010 to 24 % in 2011 after the earthquake (p < 0.05). CONCLUSION: In addition to the increased incidence of peptic ulcers, compositional changes in the disease were observed after the Great East Japan earthquake. The significant increase in the proportion of non-H. pylori and non-NSAID ulcers after the earthquake indicated that psychological stress alone induced peptic ulcers in humans independently of H. pylori infection and NSAID intake.

Helicobacter pylori induces gastric mucosal intestinal metaplasia through the inhibition of interleukin-4-mediated HMG box protein Sox2 expression.

Helicobacter pylori is a major cause of the transdifferentiation into intestinal metaplasia that may develop gastric cancer. However, the molecular pathogenesis of this transdifferentiation is poorly understood. A SRY-related HMG box protein Sox2 is an essential transcription factor of organ development in brain, lung, and stomach. Our aim of this study was to investigate the mechanism responsible for regulation of Sox2 in host Th1-dominant response to H. pylori. Sox2 protein was immunohistochemically expressed in both human oxyntic and pyloric glands with H. pylori infection, but not in intestinal metaplasia. Western immunoblotting of gastric epithelial cell lines showed that IL-4, a Th2-related cytokine, dose dependently enhanced Sox2 expression among H. pylori infection-mediated cytokines. Small changes of Sox2 expression were observed after each treatment with IFN-gamma, IL-1beta, or TNF-alpha. IL-4-mediated Sox2 induction was suppressed by the inhibition of STAT6 activation with STAT6 RNA interference, and electrophoretic mobility shift assay indicated that activation of the Sox2 promoter by IL-4 occurred through the action of STAT6. Furthermore, H. pylori and IFN-gamma inhibited the phosphorylation of STAT6, resulting in the suppression of IL-4-mediated Sox2 expression. Immunohistochemical analyses showed significantly the suppressed STAT6 activity in H. pylori-infected human gastric mucosa. Additionally, downregulation of Sox2 by knockdown experiments led to intestinal phenotype with expressions of Cdx2 and MUC2. These results suggest that H. pylori and IFN-gamma interfere with the differentiation into oxyntic and pyloric glands by the downregulation of Sox2 on IL-4/STAT6 signaling, which may contribute to the transdifferentiation into intestinal metaplasia.