cyclin-d1 and Gastritis

Space radiation-induced gastrointestinal (GI) cancer risk models for future interplanetary astronauts are being developed that primarily rely on quantitative animal model studies to assess radiation-quality effects of heavy-ion space radiation exposure in relation to γ-rays. While current GI-cancer risk estimation efforts are focused on sporadic GI-cancer mouse models, emerging in-vivo data on heavy-ion radiation-induced long-term GI-inflammation are indicative of a higher but undetermined risk of GI-inflammation associated cancers, such as colitis-associated cancer (CAC). Therefore, we aimed to assess radiation quality effects on colonic inflammation, colon cancer incidence, and associated signaling events using an in-vivo CAC model i.e., Il10-/- mice. Male Il10-/- mice (8-10 weeks, n = 12/group) were irradiated with either sham, γ-rays or heavy-ions (28Si or 56Fe), and histopathological assessments for colitis and CAC were conducted at 2.5 months post-exposure. qPCR analysis for inflammation associated gene transcripts (Ptges and Tgfb1), and in-situ staining for markers of cell-proliferation (phospho-histone H3), oncogenesis (active-β-catenin, and cyclin D1), and inflammation (phospho-p65NF-κB, iNOS, and COX2) were performed. Significantly higher colitis and CAC frequency were noted after heavy-ion exposure, relative to γ and control mice. Higher CAC incidence after heavy-ion exposure was associated with greater activation of β-catenin and NF-κB signaling marked by induced expression of common downstream inflammatory (iNOS and COX2) and pro-proliferative (Cyclin D1) targets. In summary, IR-induced colitis and CAC incidence in Il10-/- mice depends on radiation quality and display co-activation of β-catenin and NF-κB signaling.

Topics: Animals; beta Catenin; Carcinogenesis; Colitis; Colonic Neoplasms; Cyclin D1; Cyclooxygenase 2; Disease Models, Animal; Gastritis; Inflammation; Male; Mice; Mice, Inbred C57BL; Neoplasms, Radiation-Induced; NF-kappa B

Helicobacter pylori infection is related to the development of gastric diseases. Various virulence factors are responsible for the pathogenic mechanisms of H. pylori infection. Our previous studies using two-dimensional gel electrophoresis showed that H. pylori thioredoxin-1 (Trx1) is overexpressed in gastric carcinomas. Here, we examined whether H. pylori Trx1 is a novel virulence factor associated with gastric tumorigenesis. We found that Trx1 expression in H. pylori isolated from gastric cancer tissues was significantly higher than that from tissues exhibiting gastritis. In the gastric epithelial cell line GES-1, infection of H. pylori with high Trx1 expression significantly induced cell apoptosis, decreased the expression of cyclin D1 and upregulated p21. However, in the gastric cancer cell line BGC823, high Trx1 expression in H. pylori significantly increased cell proliferation, and upregulated cyclin D1. The effects on cell lines were confirmed using the H. pylori Trx1-knockout mutant strain. Our observations indicate that high Trx1 expression in H. pylori is associated with gastric carcinogenesis. In H. pylori, Trx1 likely participates in the pathogenesis of gastric cancer and H. pylori expressing high levels of Trx1 would be expected to be highly pathogenic in gastric diseases in China.

Topics: Apoptosis; Bacterial Proteins; Cell Line; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; China; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Gastritis; Gene Expression Regulation, Bacterial; Gene Knockout Techniques; Helicobacter Infections; Helicobacter pylori; Humans; Mutation; Organ Specificity; Stomach Neoplasms; Thioredoxins; Up-Regulation; Virulence Factors

Gastric cancer is the second leading cause of cancer death worldwide. Predisposing factors include achlorhydria, Helicobacter pylori infection, oxyntic atrophy and TFF2-expressing metaplasia. In parietal cells, apical potassium channels comprising the KCNQ1 alpha subunit and the KCNE2 beta subunit provide a K(+) efflux current to facilitate gastric acid secretion by the apical H(+)K(+)ATPase. Accordingly, genetic deletion of murine Kcnq1 or Kcne2 impairs gastric acid secretion. Other evidence has suggested a role for KCNE2 in human gastric cancer cell proliferation, independent of its role in gastric acidification. Here, we demonstrate that 1-year-old Kcne2(-/-) mice in a pathogen-free environment all exhibit a severe gastric preneoplastic phenotype comprising gastritis cystica profunda, 6-fold increased stomach mass, increased Ki67 and nuclear Cyclin D1 expression, and TFF2- and cytokeratin 7-expressing metaplasia. Some Kcne2(-/-) mice also exhibited pyloric polypoid adenomas extending into the duodenum, and neoplastic invasion of thin walled vessels in the sub-mucosa. Finally, analysis of human gastric cancer tissue indicated reduced parietal cell KCNE2 expression. Together with previous findings, the results suggest KCNE2 disruption as a possible risk factor for gastric neoplasia.

Topics: Animals; Blotting, Western; Cell Line; Cell Line, Tumor; Cyclin D1; Fluorescent Antibody Technique; Gastric Mucosa; Gastritis; Gene Deletion; H(+)-K(+)-Exchanging ATPase; Humans; Immunohistochemistry; KCNQ1 Potassium Channel; Ki-67 Antigen; Metaplasia; Mice; Mice, Mutant Strains; Peptides; Potassium Channels, Voltage-Gated; Stomach Neoplasms; Trefoil Factor-2

Cyclin D1 (CCND1) is known to regulate function in G1 arrest and therefore may play an important role in carcinogenesis. The aim of this study was to investigate the effect of G870A polymorphism of the CCND1 gene on gastric precancerous condition, on histological chronic gastritis, and on the risk of peptic ulcer diseases.. Restriction fragment length polymorphism analysis was performed for polymorphisms at 870GA in the CCND1 gene in 524 cancer-free subjects, including 111 gastric and 54 duodenal ulcers, and 359 non-ulcer subjects. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system in 384 subjects.. CCND1 genotype was significantly associated with the severity of intestinal metaplasia by the Kruskal-Wallis test, and this tendency was especially stronger among older subjects of 61 years or older (overall subjects: p=0.035, 61 years approximately : p=0.007). We also found that the 870AA genotype held a significant high risk of intestinal metaplasia [Helicobacter pylori infection adjusted odds ratio (OR)=1.8, 95% confidence interval (CI)=1.03-3.15, p=0.04]. The same genotype was more closely associated with the risk of intestinal metaplasia in older subjects of 61 years or older (H. pylori infection adjusted OR=3.45, 95% CI=1.48-8.08, p=0.004). A non-significant association was found between CCND1 G870A genotypes and the risk of peptic ulcer diseases as well as histological severity of acute or chronic inflammation.. It appears that the G870A polymorphism of CCND1 is associated with gastric premalignant condition especially in older subjects.

Topics: Cyclin D1; Female; Gastritis; Genetic Predisposition to Disease; Humans; Japan; Male; Middle Aged; Peptic Ulcer; Polymorphism, Genetic; Precancerous Conditions; Severity of Illness Index; Stomach Neoplasms

We have characterized an experimental model of ethanol-induced chronic gastritis in which a compensatory mucosal cell proliferation is apparently regulated by lipoperoxidative events. Therefore, the present study is an attempt to further assess the participation of oxidant stress during gastric mucosa proliferation, by administering alpha-tocopherol (vitamin E) to rats with gastritis. A morphometric analysis was done, and parameters indicative of oxidant stress, cellular proliferation (including cyclin D1 levels), apoptotic events, and activities of endogenous antioxidant systems were measured in gastric mucosa from our experimental groups. After ethanol withdrawal, restitution of surface epithelium coincided with increased lipid peroxidation and cell proliferation and further active apoptosis. High alpha-tocopherol dosing (100 IU/kg bw) showed a clear antioxidant effect, abolished cell proliferation, and promoted an early and progressive apoptosis, despite vitamin E also enhancing levels of endogenous antioxidants. Indicators of cell proliferation inversely correlated with apoptotic events, and this relationship was blunted by administering vitamin E, probably by affecting translocation of active cyclin D1 into the nucleus. In conclusion, alpha-tocopherol administration inhibited cell proliferation, leading to a predominance of apoptotic events in ethanol-induced gastric damage. Therefore, the timing and magnitude of lipoperoxidative events seemed to synchronize in vivo cell proliferative and apoptotic events, probably by changing the cell redox state.

Topics: alpha-Tocopherol; Animals; Antioxidants; Apoptosis; Cell Proliferation; Cyclin D1; DNA; Gastric Mucosa; Gastritis; Male; Oxidative Stress; Rats; Rats, Wistar; Thiobarbituric Acid Reactive Substances; Vitamin E

Changes in proliferation and apoptosis parameters of the gastric epithelium in patients with chronic Hp-associated gastritis were studied depending on the prevalence of the inflammatory process, presence of intestinal metaplasia and atrophic changes of the stomach glandular epithelium. The obtained results demonstrated a change in the cellular updating processes of the stomach epithelium depending on the localization, prevalence of the process, and more expressed - during the development of atrophic and dystrophic changes of the stomach mucous coat. Moderate amplification of apoptosis was recorded in focal atrophic gastritis, which was shown in the increased Iapopt and reduction of IPCNA and IcyclineD1 parameters. From then on, along with the distribution of the process, proliferation enhancement, occurrences of intestinal metaplasia and neoplasia centers, oppression of apoptosis destructions of stomach epitheliocytes was marked.

Topics: Adult; Aged; Apoptosis; Cell Proliferation; Cyclin D1; Female; Gastric Mucosa; Gastritis; Helicobacter; Humans; Male; Middle Aged; Precancerous Conditions; Proliferating Cell Nuclear Antigen; Stomach Neoplasms

To clarify the role of these cyclins in human gastric cancer.. 38 gastric cancer patients, 29 first degree relatives of gastric cancer patients, as well as 18 healthy subjects were included. The mRNA expression of cyclins D1, D2, D3 and E in gastric biopsies was evaluated by RT-PCR analysis using specific primers. Histomorphological features such as intestinal metaplasia, atrophy, H. pylori infection and severity of gastritis were determined by the updated Sydney System.. Significant mRNA overexpression was found for cyclins D2, D3 and E compared with healthy normal specimen, but cyclin D1 expression was not different between tumor and normal tissues. In addition, cyclin D2 and D3 overexpression was significantly more frequent in first degree relatives than in healthy controls (P < 0.05). Among the various pathological findings, the overexpression of cyclins D2 and E was associated with intestinal metaplasia, and the overexpression of cyclin D3 was associated with intestinal metaplasia as well as atrophy. The overexpression of cyclins D2 and D3 was significantly correlated with H. pylori infection. No correlation was observed between the overexpression of cyclin D1 and any pathological variables.. The overexpression of cyclins D2, D3 and E is a frequent event in patients with gastric cancer and their first degree relatives and may be an early event in gastric carcinogenesis.

Topics: Adult; Aged; Aged, 80 and over; Cyclin D1; Cyclin D2; Cyclin D3; Cyclin E; Cyclins; Family Health; Gastric Mucosa; Gastritis; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Helicobacter pylori; Humans; Middle Aged; RNA, Messenger; Stomach; Stomach Neoplasms

Helicobacter pylori (H. pylori) infection is associated with changes in epithelial turnover, through their significance of these in gastric carcinogenesis is still controversial. The purpose of this study was to determine the influence of H. pylori infection on cell proliferation and the relation with the cell-cycle regulators, and finally to provide insights into the mechanism by which H. pylori may lead to gastric carcinogenesis. We investigated Ki-67, p53, p21(Waf1/Cip1), cyclin D1 expression in 55 patients with H. pylori gastritis, and compared the results with patients those of non-H. pylori gastritis patients (n=21), gastric adenocarcinoma patients (n=8) and samples with normal gastric mucosa (n=12). Gastric biopsies were histologically evaluated for inflammatory reaction, intestinal metaplasia and atrophy according to the Sydney system. Overexpression of Ki-67, p53, p21(Waf1/Cip1) and cyclin D1 was found in H. pylori gastritis patients (32.7%, 10.9%, 20.0% and 7.3%, respectively), whereas only scattered expression in cells in the neck region of the crypts, but no overexpression was found in gastric antral epithelial cells in biopsy specimens from patients with non-H. pylori gastritis and noninflammed mucosa. A significant relationship was found between the grade of H. pylori colonization and Ki-67, p53, p21(Waf1/Cip1) and cyclin D1 expression. Expression was significantly higher in patients with intestinal metaplasia with atrophy, whereas no overexpression was found in patients without intestinal metaplasia with atrophy (p=0.05). H. pylori infection is associated with increased cell proliferation, increased epithelial DNA damage, and atrophy, which might contribute to the development of gastric cancer. Even if the exact mechanism has not been elucidated yet, our results suggest that H. pylori infection acts as a cofactor in gastric carcinogenesis.

Topics: Adenocarcinoma; Biopsy; Cell Cycle; Cell Cycle Proteins; Cell Division; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Gastric Mucosa; Gastritis; Helicobacter Infections; Helicobacter pylori; Humans; Ki-67 Antigen; Reference Values; Stomach Neoplasms; Tumor Suppressor Protein p53