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Sample records for gastric carcinogenesis induced

  1. Effect of Helicobacter pylori-induced cyclooxygenase-2 on gastric epithelial cell kinetics: implication for gastric carcinogenesis.

    PubMed

    Wambura, Casmir; Aoyama, Nobuo; Shirasaka, Daisuke; Sakai, Toshiyuki; Ikemura, Takahiro; Sakashita, Masanori; Maekawa, Shuji; Kuroda, Kohei; Inoue, Takashi; Ebara, Shigeyuki; Miyamoto, Masaki; Kasuga, Masato

    2002-04-01

    Cyclooxygenase (COX)-2 induced by Helicobacter pylori is thought to enhance gastric carcinogenesis by affecting the maintenance of epithelial homeostasis. Gastric biopsies from 160 subjects, 97 with nonulcer dyspepsia (47 H. pylori negative, 50 H. pylori positive) and 63 with gastric cancer were examined immunohistochemically for COX-2 expression, cell proliferation and apoptotic indices. COX-2 expression in corpus was significantly higher in H. pylori positive than in negative non-ulcer dyspepsia (NUD) (p <.05). Regardless of site, gastric cancer subjects had higher COX-2 expression in both antrum and corpus compared with H. pylori negative and positive NUD (p <.005). Proliferation was higher in cancer and H. pylori positive than in negative NUD (p <.0001). Moreover, cancer had enhanced proliferation than H. pylori positive NUD in corpus greater (p =.0454) and antrum lesser (p =.0215) curvatures. Apoptosis was higher in H. pylori positive than in negative NUD (p <.05). However, both had a higher index than the cancer subjects (p <.0001). Apoptosis : proliferation ratio was higher in corpus of H. pylori negative than in positive NUD in greater (p =.0122) and lesser (p =.0009) curvatures. However, both had a higher A:P ratio than cancer cases (p =.0001). A negative correlation between COX-2 expression and A:P ratio was found in corpus greater (r = -.176, p =.0437) and lesser (r = -.188, p =.0312) curvatures. The expression of COX-2 is associated with disruption in gastric epithelial kinetics and hence may play a role in gastric carcinogenesis.

  2. Spermine oxidation induced by Helicobacter pylori results in apoptosis and DNA damage: implications for gastric carcinogenesis.

    PubMed

    Xu, Hangxiu; Chaturvedi, Rupesh; Cheng, Yulan; Bussiere, Francoise I; Asim, Mohammad; Yao, Micheal D; Potosky, Darryn; Meltzer, Stephen J; Rhee, Juong G; Kim, Sung S; Moss, Steven F; Hacker, Amy; Wang, Yanlin; Casero, Robert A; Wilson, Keith T

    2004-12-01

    Oxidative stress is linked to carcinogenesis due to its ability to damage DNA. The human gastric pathogen Helicobacter pylori exerts much of its pathogenicity by inducing apoptosis and DNA damage in host gastric epithelial cells. Polyamines are abundant in epithelial cells, and when oxidized by the inducible spermine oxidase SMO(PAOh1) H(2)O(2) is generated. Here, we report that H. pylori up-regulates mRNA expression, promoter activity, and enzyme activity of SMO(PAOh1) in human gastric epithelial cells, resulting in DNA damage and apoptosis. H. pylori-induced H(2)O(2) generation and apoptosis in these cells was equally attenuated by an inhibitor of SMO(PAOh1), by catalase, and by transient transfection with small interfering RNA targeting SMO(PAOh1). Conversely, SMO(PAOh1) overexpression induced apoptosis to the same levels as caused by H. pylori. Importantly, in H. pylori-infected tissues, there was increased expression of SMO(PAOh1) in both human and mouse gastritis. Laser capture microdissection of human gastric epithelial cells demonstrated expression of SMO(PAOh1) that was significantly attenuated by H. pylori eradication. These results identify a pathway for oxidative stress-induced epithelial cell apoptosis and DNA damage due to SMO(PAOh1) activation by H. pylori that may contribute to the pathogenesis of the infection and development of gastric cancer.

  3. Diet Synergistically Affects Helicobacter pylori-Induced Gastric Carcinogenesis in Non-human Primates

    PubMed Central

    Liu, Hui; Merrell, D. Scott; Semino-Mora, Cristina; Goldman, Matthew; Rahman, Arifur; Mog, Steven; Dubois, Andre

    2009-01-01

    Background and Aims Gastric cancer results from a combination of H. pylori infection, exposure to dietary carcinogens, and predisposing genetic makeup. Because the role of these factors in gastric carcinogenesis cannot be readily determined in humans, the present study examined the role of an oral carcinogen and H. pylori infection in Rhesus monkeys. Methods Gastroscopies were performed in 23 monkeys assigned to four groups: controls (C); nitrosating carcinogen ethyl-nitro-nitrosoguanidine (ENNG) administration alone (E); inoculation of a virulent H. pylori strain, alone (H); and ethyl-nitro-nitrosoguanidine in combination with H. pylori (EH). Follow-up gastroscopies and biopsies were performed at 3-month intervals for five years for pathological and molecular studies. Results Postinoculation, H and EH groups exhibited persistent infection and antral gastritis. Starting at two- and five-year, respectively, gastric intestinal metaplasia and intraepithelial neoplasia developed in three EH monkeys but in no other groups. Transcriptional analysis of biopsy specimens at five-year revealed group-specific expression profiles, with striking changes in EH monkeys, plus a neoplasia-specific expression profile characterized by changes in multiple cancer-associated genes. Importantly, this neoplastic profile was evident in non-neoplastic mucosa, suggesting that the identified genes may represent markers preceding cancer. Conclusions Gastric intraglandular neoplasia is induced in primates when H. pylori infection is associated with consumption of a carcinogen similar to the nitrosamines found in pickled vegetables, suggesting that H. pylori and the carcinogen synergistically induce gastric neoplasia in primates. PMID:19622359

  4. High Dietary Salt Intake Exacerbates Helicobacter pylori-Induced Gastric Carcinogenesis

    PubMed Central

    Gaddy, Jennifer A.; Radin, Jana N.; Loh, John T.; Zhang, Feng; Washington, M. Kay; Peek, Richard M.; Algood, Holly M. Scott

    2013-01-01

    Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pylori-induced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA+ H. pylori strain or an isogenic cagA mutant strain and maintained the animals on a regular diet or a high-salt diet. At 4 months postinfection, gastric adenocarcinoma was detected in 100% of the WT-infected/high-salt-diet animals, 58% of WT-infected/regular-diet animals, and none of the animals infected with the cagA mutant strain (P < 0.0001). Among animals infected with the WT strain, those fed a high-salt diet had more severe gastric inflammation, higher gastric pH, increased parietal cell loss, increased gastric expression of interleukin 1β (IL-1β), and decreased gastric expression of hepcidin and hydrogen potassium ATPase (H,K-ATPase) compared to those on a regular diet. Previous studies have detected upregulation of CagA synthesis in response to increased salt concentrations in the bacterial culture medium, and, concordant with the in vitro results, we detected increased cagA transcription in vivo in animals fed a high-salt diet compared to those on a regular diet. Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA+ H. pylori strains. PMID:23569116

  5. High dietary salt intake exacerbates Helicobacter pylori-induced gastric carcinogenesis.

    PubMed

    Gaddy, Jennifer A; Radin, Jana N; Loh, John T; Zhang, Feng; Washington, M Kay; Peek, Richard M; Algood, Holly M Scott; Cover, Timothy L

    2013-06-01

    Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pylori-induced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA(+) H. pylori strain or an isogenic cagA mutant strain and maintained the animals on a regular diet or a high-salt diet. At 4 months postinfection, gastric adenocarcinoma was detected in 100% of the WT-infected/high-salt-diet animals, 58% of WT-infected/regular-diet animals, and none of the animals infected with the cagA mutant strain (P < 0.0001). Among animals infected with the WT strain, those fed a high-salt diet had more severe gastric inflammation, higher gastric pH, increased parietal cell loss, increased gastric expression of interleukin 1β (IL-1β), and decreased gastric expression of hepcidin and hydrogen potassium ATPase (H,K-ATPase) compared to those on a regular diet. Previous studies have detected upregulation of CagA synthesis in response to increased salt concentrations in the bacterial culture medium, and, concordant with the in vitro results, we detected increased cagA transcription in vivo in animals fed a high-salt diet compared to those on a regular diet. Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA(+) H. pylori strains.

  6. Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response

    PubMed Central

    Ericksen, Russell E; Rose, Shannon; Westphalen, Christoph Benedikt; Shibata, Wataru; Muthupalani, Sureshkumar; Tailor, Yagnesh; Friedman, Richard A; Han, Weiping; Fox, James G; Ferrante, Anthony W; Wang, Timothy C

    2014-01-01

    Objective To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. Design C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. Results H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. Conclusions Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment. PMID:23729675

  7. Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response.

    PubMed

    Ericksen, Russell E; Rose, Shannon; Westphalen, Christoph Benedikt; Shibata, Wataru; Muthupalani, Sureshkumar; Tailor, Yagnesh; Friedman, Richard A; Han, Weiping; Fox, James G; Ferrante, Anthony W; Wang, Timothy C

    2014-03-01

    To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony-stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment.

  8. Helicobacter pylori in gastric carcinogenesis

    PubMed Central

    Ahn, Hyo Jun; Lee, Dong Soo

    2015-01-01

    Gastric cancer still is a major concern as the third most common cancer worldwide, despite declining rates of incidence in many Western countries. Helicobacter pylori (H. pylori) is the major cause of gastric carcinogenesis, and its infection insults gastric mucosa leading to the occurrence of atrophic gastritis which progress to intestinal metaplasia, dysplasia, early gastric cancer, and advanced gastric cancer consequently. This review focuses on multiple factors including microbial virulence factors, host genetic factors, and environmental factors, which can heighten the chance of occurrence of gastric adenocarcinoma due to H. pylori infection. Bacterial virulence factors are key components in controlling the immune response associated with the induction of carcinogenesis, and cagA and vacA are the most well-known pathogenic factors. Host genetic polymorphisms contribute to regulating the inflammatory response to H. pylori and will become increasingly important with advancing techniques. Environmental factors such as high salt and smoking may also play a role in gastric carcinogenesis. It is important to understand the virulence factors, host genetic factors, and environmental factors interacting in the multistep process of gastric carcinogenesis. To conclude, prevention via H. pylori eradication and controlling environmental factors such as diet, smoking, and alcohol is an important strategy to avoid H. pylori-associated gastric carcinogenesis. PMID:26690981

  9. Autophagy impairment by Helicobacter pylori-induced methylation silencing of MAP1LC3Av1 promotes gastric carcinogenesis.

    PubMed

    Muhammad, Jibran Sualeh; Nanjo, Sohachi; Ando, Takayuki; Yamashita, Satoshi; Maekita, Takao; Ushijima, Toshikazu; Tabuchi, Yoshiaki; Sugiyama, Toshiro

    2017-05-15

    Helicobacter pylori (H. pylori) infection induces methylation silencing of tumor suppressor genes causing gastric carcinogenesis. Impairment of autophagy induces DNA damage leading to genetic instability and carcinogenesis. We aimed to identify whether H. pylori infection induced methylation silencing of host autophagy-related (Atg) genes, impairing autophagy and enhancing gastric carcinogenesis. Gastric mucosae were obtained from 41 gastric cancer patients and 11 healthy volunteers (8 H. pylori-uninfected and 3 H. pylori-infected). Methylation status of Atg genes was analyzed by a methylation microarray and quantitative methylation-specific PCR (qMSP); mRNA expression was assessed by quantitative reverse transcription PCR (qRT-PCR). Cell proliferation, migration and invasion were assessed in normal rat gastric epithelial cells. Gene knock-down was performed by siRNA. Autophagy was assessed by western blotting. Of 34 Atg genes, MAP1LC3A variant 1 (MAP1LC3Av1) and ULK2 were identified by methylation microarray analysis as exhibiting specific methylation in H. pylori-infected mucosae and gastric cancer tissues. Methylation silencing of MAP1LC3Av1 was confirmed by qMSP, qRT-PCR and de-methylation treatment in two gastric cancer cell lines. Knock-down of map1lc3a, the rat homolog of the human MAP1LC3Av1, inhibited autophagy response and increased cell proliferation, migration and invasion in normal rat gastric epithelial cells, despite the presence of map1lc3b, the rat homolog of the human MAP1LC3B gene important for autophagy. Furthermore, MAP1LC3Av1 was methylation-silenced in 23.3% of gastric cancerous mucosae and 40% of non-cancerous mucosae with H. pylori infection. MAP1LC3Av1 is essential for autophagy and H. pylori-induced methylation silencing of MAP1LC3Av1 may impair autophagy, facilitating gastric carcinogenesis.

  10. Mouse Models of Gastric Carcinogenesis

    PubMed Central

    Yu, Sungsook; Yang, Mijeong

    2014-01-01

    Gastric cancer is one of the most common cancers in the world. Animal models have been used to elucidate the details of the molecular mechanisms of various cancers. However, most inbred strains of mice have resistance to gastric carcinogenesis. Helicobacter infection and carcinogen treatment have been used to establish mouse models that exhibit phenotypes similar to those of human gastric cancer. A large number of transgenic and knockout mouse models of gastric cancer have been developed using genetic engineering. A combination of carcinogens and gene manipulation has been applied to facilitate development of advanced gastric cancer; however, it is rare for mouse models of gastric cancer to show aggressive, metastatic phenotypes required for preclinical studies. Here, we review current mouse models of gastric carcinogenesis and provide our perspectives on future developments in this field. PMID:25061535

  11. JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression

    PubMed Central

    Zhang, Jinjin; Sun, Yundong; Ma, Fang; Liu, Zhifang; Yu, Han; Jia, Jihui; Li, Wenjuan

    2016-01-01

    Helicobacter pylori (H. pylori) infection is the strongest risk factor for the initiation and progression of gastric cancer. However, the mechanism of H. pylori-induced pathogenesis remains unclear. In this study, we investigate the role of H. pylori infection in JMJD2B upregulation and the mechanism underlying gastric carcinogenesis. We find that JMJD2B can be induced by H. pylori infection via β-catenin pathway. β-catenin directly binds to JMJD2B promoter and stimulates JMJD2B expression following H. pylori infection. Increased JMJD2B, together with NF-κB, binds to COX-2 promoter to enhance its transcription by demethylating H3K9me3 locally. JMJD2B and COX-2 expression is upregulated in H. pylori infected mice in vivo. Furthermore, JMJD2B and COX-2 expression is gradually increased in human gastric tissues from gastritis to gastric cancer. The level of JMJD2B and COX-2 in H. pylori-positive gastritis tissues is significantly higher than that in H. pylori-negative tissues. Moreover, a positive correlation between JMJD2B and COX-2 expression is found in both gastritis and gastric cancer tissues. Therefore, JMJD2B is a crucial factor in triggering H. pylori-induced chronic inflammation and progression of gastric carcinogenesis and it may serve as a novel target for the intervention of gastric cancer. PMID:27232941

  12. JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression.

    PubMed

    Han, Fengjuan; Ren, Juchao; Zhang, Jinjin; Sun, Yundong; Ma, Fang; Liu, Zhifang; Yu, Han; Jia, Jihui; Li, Wenjuan

    2016-06-21

    Helicobacter pylori (H. pylori) infection is the strongest risk factor for the initiation and progression of gastric cancer. However, the mechanism of H. pylori-induced pathogenesis remains unclear. In this study, we investigate the role of H. pylori infection in JMJD2B upregulation and the mechanism underlying gastric carcinogenesis. We find that JMJD2B can be induced by H. pylori infection via β-catenin pathway. β-catenin directly binds to JMJD2B promoter and stimulates JMJD2B expression following H. pylori infection. Increased JMJD2B, together with NF-κB, binds to COX-2 promoter to enhance its transcription by demethylating H3K9me3 locally. JMJD2B and COX-2 expression is upregulated in H. pylori infected mice in vivo. Furthermore, JMJD2B and COX-2 expression is gradually increased in human gastric tissues from gastritis to gastric cancer. The level of JMJD2B and COX-2 in H. pylori-positive gastritis tissues is significantly higher than that in H. pylori-negative tissues. Moreover, a positive correlation between JMJD2B and COX-2 expression is found in both gastritis and gastric cancer tissues. Therefore, JMJD2B is a crucial factor in triggering H. pylori-induced chronic inflammation and progression of gastric carcinogenesis and it may serve as a novel target for the intervention of gastric cancer.

  13. Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis.

    PubMed

    Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G; Piazuelo, M Blanca; Suarez, Giovanni; Romero-Gallo, Judith; Delgado, Alberto G; Wroblewski, Lydia E; Barry, Daniel P; Peek, Richard M; Gobert, Alain P; Wilson, Keith T

    2017-05-04

    Gastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis. We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr (Efgr(Δepi) mice) were also used. In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected Egfr(Δepi) versus Egfr(fl/fl) control mice. In H. pylori-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylori-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from Efgr(Δepi) versus Egfr(fl/fl) mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics. These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori-infected individuals. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  14. Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis.

    PubMed

    Valenzuela, Manuel A; Canales, Jimena; Corvalán, Alejandro H; Quest, Andrew F G

    2015-12-07

    The sequence of events associated with the development of gastric cancer has been described as "the gastric precancerous cascade". This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context.

  15. Helicobacter pylori-induced inflammation and epigenetic changes during gastric carcinogenesis

    PubMed Central

    Valenzuela, Manuel A; Canales, Jimena; Corvalán, Alejandro H; Quest, Andrew FG

    2015-01-01

    The sequence of events associated with the development of gastric cancer has been described as “the gastric precancerous cascade”. This cascade is a dynamic process that includes lesions, such as atrophic gastritis, intestinal metaplasia and dysplasia. According to this model, Helicobacter pylori (H. pylori) infection targets the normal gastric mucosa causing non-atrophic gastritis, an initiating lesion that can be cured by clearing H. pylori with antibiotics or that may then linger in the case of chronic infection and progress to atrophic gastritis. The presence of virulence factors in the infecting H. pylori drives the carcinogenesis process. Independent epidemiological and animal studies have confirmed the sequential progression of these precancerous lesions. Particularly long-term follow-up studies estimated a risk of 0.1% for atrophic gastritis/intestinal metaplasia and 6% in case of dysplasia for the long-term development of gastric cancer. With this in mind, a better understanding of the genetic and epigenetic changes associated with progression of the cascade is critical in determining the risk of gastric cancer associated with H. pylori infection. In this review, we will summarize some of the most relevant mechanisms and focus predominantly but not exclusively on the discussion of gene promoter methylation and miRNAs in this context. PMID:26668499

  16. Helicobacter pylori-induced modulation of the promoter methylation of Wnt antagonist genes in gastric carcinogenesis.

    PubMed

    Yang, Hyo-Joon; Kim, Sang Gyun; Lim, Joo Hyun; Choi, Ji Min; Kim, Woo Ho; Jung, Hyun Chae

    2017-06-22

    This study aimed to investigate the changes in the promoter methylation and gene expression of multiple Wnt antagonists between the chronic infection and eradication of Helicobacter pylori (H. pylori) in gastric carcinogenesis. The levels of methylation and corresponding mRNA expression of seven Wnt antagonist genes (SFRP1, -2, -5, DKK1, -2, -3, WIF1) were compared among the patients with H. pylori-positive gastric cancers (GCs), and H. pylori-positive and H. pylori-negative controls, by quantitative MethyLight assay and real-time reverse transcription (RT)-polymerase chain reaction (PCR), respectively. The changes of the methylation and expression levels of the genes were also compared between the H. pylori eradication and H. pylori-persistent groups 1 year after endoscopic resection of GCs. The methylation levels of SFRP and DKK family genes were significantly increased in the patients with H. pylori-positive GCs and followed by H. pylori-positive controls compared with H. pylori-negative controls (P < 0.001). SFRP1, -2, and DKK3 gene expression was stepwise downregulated from H. pylori-negative controls, H. pylori-positive controls, and to H. pylori-positive GCs (P < 0.05). Among the Wnt antagonists, only the degrees of methylation and downregulation of DKK3 were significantly reduced after H. pylori eradication (P < 0.05). Epigenetic silencing of SFRP and DKK family genes may facilitate the formation of an epigenetic field during H. pylori-associated gastric carcinogenesis. The epigenetic field may not be reversed even after H. pylori eradication except by DKK3 methylation.

  17. Deoxycholic Acid Could Induce Apoptosis and Trigger Gastric Carcinogenesis on Gastric Epithelial Cells by Quantitative Proteomic Analysis

    PubMed Central

    Wei, Ying; Zhang, Jing; Wang, Ye

    2016-01-01

    Background. Pathologic duodenogastric reflux can induce or aggravate gastritis because of the presence of bile acids. Bile reflux has been generally considered to be associated with intestinal metaplasia and gastric cancer. However, the pathogenic mechanisms of the effects of bile acids on gastric mucosa are still unknown. Methods. To explore the mechanisms by which bile acids induce gastric mucosal lesions, we examined cell apoptosis in the gastric epithelial cell line GES-1 and investigated the changes in protein profiles of GES-1 cells in response to a bile acid deoxycholic acid using a proteomics approach. Changes in the profiles of the differently expressed proteins were analyzed using the DAVID and STRING programs. Results. We found apoptosis was significantly induced in GES-1 cells by deoxycholic acid. Using liquid chromatographic/tandem mass spectrometric (LC-MS/MS) methods, 134 upregulated proteins and 214 downregulated proteins were identified in the bile acid treated GES-1 cells. Bioinformatics analysis revealed the interactions and signaling networks of these differentially expressed proteins. Conclusion. These findings may improve the understanding of the molecular mechanisms underlying the pathogenicity of bile acids on gastric mucosa. PMID:28070185

  18. Anticancer Effect of Lycopene in Gastric Carcinogenesis

    PubMed Central

    Kim, Mi Jung; Kim, Hyeyoung

    2015-01-01

    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. PMID:26151041

  19. Effect of Dendrobium officinale Extraction on Gastric Carcinogenesis in Rats

    PubMed Central

    Liu, Yan; Lan, Xi-Ming; Xu, Guo-Liang; Sun, You-Zhi; Li, Fei

    2016-01-01

    Dendrobium officinale (Tie Pi Shi Hu in Chinese) has been widely used to treat different diseases in China. Anticancer effect is one of the important effects of Dendrobium officinale. However, the molecular mechanism of its anticancer effect remains unclear. In the present study, gastric carcinogenesis in rats was used to evaluate the effect of Dendrobium officinale on cancer, and its pharmacological mechanism was explored. Dendrobium officinale extracts (4.8 and 2.4 g/kg) were orally administered to the rats of the gastric carcinogenesis model. Compared with the cancer model group, the high dose of Dendrobium officinale extracts significantly inhibited the rate of carcinogenesis. Further analysis revealed that Dendrobium officinale extracts could regulate the DNA damage, oxidative stress, and cytokines related with carcinogenesis and induce cell apoptosis in order to prevent gastric cancer. PMID:28119756

  20. Attenuation by genistein of sodium-chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

    PubMed

    Tatsuta, M; Iishi, H; Baba, M; Yano, H; Uehara, H; Nakaizumi, A

    1999-01-29

    The effects of prolonged administration of genistein, a tyrosine-kinase inhibitor, on sodium-chloride-enhanced induction of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labeling and apoptotic indices and vessel counts in the gastric mucosa and gastric cancers, were investigated in Wistar rats. After 25 weeks of the carcinogen treatment, rats were fed chow pellets containing 10% sodium chloride and were given s.c. injections of genistein at dosages of 15 mg/kg or 30 mg/kg body weight every other day. In week 52, the incidence of gastric cancers was significantly greater in rats fed sodium chloride than in untreated control rats. Prolonged administration of genistein at a dosage of 30 mg/kg, but not 15 mg/kg, body weight significantly reduced the incidence of gastric cancers, which was increased by oral treatment with sodium chloride. Genistein at the higher dose significantly decreased the labeling index and vessel counts of the antral mucosa and the gastric cancers (which were increased by treatment with sodium chloride) and significantly increased the apoptotic index of the antral mucosa and the cancers (which was lowered by the treatment with sodium chloride). These findings suggest that genistein attenuates gastric carcinogenesis promoted by sodium chloride, by inducing increased apoptosis and lower cell proliferation and angiogenesis of antral mucosa and gastric cancers.

  1. Preventive effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats.

    PubMed

    Tsukamoto, Hironobu; Mizoshita, Tsutomu; Katano, Takahito; Hayashi, Noriyuki; Ozeki, Keiji; Ebi, Masahide; Shimura, Takaya; Mori, Yoshinori; Tanida, Satoshi; Kataoka, Hiromi; Tsukamoto, Tetsuya; Tatematsu, Masae; Joh, Takashi

    2015-03-01

    Chemoprevention strategies against gastric cancer (GC) need to be explored in light of the fact that stomach cancer still occurs in the absence of Helicobacter pylori (HP) infection and following HP eradication. We evaluated the effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in SD rats. Thirty-nine male rats were divided into four groups based on whether or not they were treated with rebamipide and/or MNNG: Control, Rebamipide, Control-M, and Rebamipide-M groups. From 8 weeks of age, rats in the Control-M and Rebamipide-M groups received MNNG in drinking water for 30 weeks. The Rebamipide and Rebamipide-M groups were administered 5mg/kg/day of rebamipide. At 50 weeks, cancerous lesions were not observed in either the Control or Rebamipide groups. Nine rats in the Control-M group had developed GC, while four rats in the Rebamipide-M group had developed GC. The incidence of cancer in the Rebamipide-M group was significantly less than in the Control-M group (p<0.05), with a trend toward a lower incidence of invasive carcinoma in the Rebamipide-M group. Carcinomatous invasion into the muscularis propria was not observed in the Rebamipide-M group. In conclusion, the present study demonstrates that rebamipide suppresses. MNNG-induced carcinogenesis and may also inhibit progression of cancer in rats.

  2. Suppression by iron chelator phenanthroline of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

    PubMed

    Tatsuta, Masaharu; Iishi, Hiroyasu; Baba, Miyako; Mikuni, Tomiko; Narahara, Hiroyuki; Uedo, Noriya; Yano, Hiroyuki

    2003-02-28

    The effect of prolonged administration of iron chelator phenanthroline on sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine, and the labeling and apoptotic indices in the gastric cancers was investigated in Wistar rats. After 25 weeks of carcinogen treatment, the rats were given chow pellets containing 10% sodium chloride and intraperitoneal injections of phenanthroline at doses of 15 or 30 mg/kg body weight every other day. At week 52, feeding of sodium chloride significantly increased the incidence of gastric cancers, as compared with the control group. Prolonged injections of phenanthroline at both doses significantly reduced the incidence of gastric cancers, which was enhanced by oral supplementation with sodium chloride. Phenanthroline at both doses significantly decreased the labeling index of gastric cancers, which was enhanced by sodium chloride, and significantly increased the apoptotic index of gastric cancers, which was lowered by sodium chloride. In vitro examination using electron spin resonance revealed that sodium chloride promotes the production of hydroxyl radical during Fe(2+) oxidation by Fenton's reaction. These findings suggest that enhancement by sodium chloride of gastric carcinogenesis may be mediated by hydroxyl radicals.

  3. What gastric cancer proteomic studies show about gastric carcinogenesis?

    PubMed

    Leal, Mariana Ferreira; Wisnieski, Fernanda; de Oliveira Gigek, Carolina; do Santos, Leonardo Caires; Calcagno, Danielle Queiroz; Burbano, Rommel Rodriguez; Smith, Marilia Cardoso

    2016-08-01

    Gastric cancer is a complex, heterogeneous, and multistep disease. Over the past decades, several studies have aimed to determine the molecular factors that lead to gastric cancer development and progression. After completing the human genome sequencing, proteomic technologies have presented rapid progress. Differently from the relative static state of genome, the cell proteome is dynamic and changes in pathologic conditions. Proteomic approaches have been used to determine proteome profiles and identify differentially expressed proteins between groups of samples, such as neoplastic and nonneoplastic samples or between samples of different cancer subtypes or stages. Therefore, proteomic technologies are a useful tool toward improving the knowledge of gastric cancer molecular pathogenesis and the understanding of tumor heterogeneity. This review aimed to summarize the proteins or protein families that are frequently identified by using high-throughput screening methods and which thus may have a key role in gastric carcinogenesis. The increased knowledge of gastric carcinogenesis will clearly help in the development of new anticancer treatments. Although the studies are still in their infancy, the reviewed proteins may be useful for gastric cancer diagnosis, prognosis, and patient management.

  4. In-vivo evaluation of apocynin for prevention of Helicobacter pylori-induced gastric carcinogenesis.

    PubMed

    Horemans, Tessa; Boulet, Gaëlle; van Kerckhoven, Marian; Bogers, Johannes; Thys, Sofie; Vervaet, Chris; Vervaeck, Anouck; Delputte, Peter; Maes, Louis; Cos, Paul

    2017-01-01

    The emergence of antibiotic-resistant Helicobacter pylori strains impacts the efficacy of eradication therapy and promotes the development of alternative treatment strategies. Apocynin inhibits neutrophil NADPH oxidase and hence may decrease reactive oxygen species-mediated tissue damage in H. pylori-infected stomach tissue. Apocynin was tested in vitro for its cytotoxic and direct antibacterial effects. The therapeutic efficacy of orally administered apocynin (100 mg/kg/day through drinking water or 200 mg/kg/day through combined administration of drinking water and slow-release formulation) was assessed at 9 weeks after infection in the Mongolian gerbil model. Bacterial burdens were quantified by viable plate count and quantitative PCR. Histopathological evaluation of antrum and pylorus provided insight into mucosal inflammation and injury. Apocynin showed no cytotoxic or direct antibacterial effects in vitro or in vivo. Nine weeks of apocynin treatment at 200 mg/kg/day reduced active H. pylori gastritis as neutrophil infiltration in the mucous neck region and pit abscess formation decreased significantly. In our gerbil model, prolonged high-dose apocynin treatment significantly improved H. pylori-induced pit abscess formation without indications of drug toxicity and thus further investigation of the dosage regimen and formulation and the long-term impact on neoplastic development should be carried out.

  5. Attenuation by d-limonene of sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

    PubMed

    Yano, H; Tatsuta, M; Iishi, H; Baba, M; Sakai, N; Uedo, N

    1999-08-27

    The effects of prolonged administration of d-limonene, a monocyclic monoterpene, on sodium chloride-enhanced induction of gastric carcinogenesis by N-methyl-N'-nitro-N-nitrosoguanidine, the labeling and apoptotic indices, and ornithine decarboxylase (ODC) activity of gastric cancers were investigated in Wistar rats. After 25 weeks of carcinogen treatment, rats were given chow pellets containing 10% sodium chloride and 1% limonene ad libitum. In week 52, the incidence of gastric cancers, the labeling index and ODC activity were significantly higher and the apoptotic index was significantly lower in rats given sodium chlolide than in untreated control rats. However, in rats given both sodium chloride and d-limonene, the incidence of gastric cancers, the labeling index and ODC activity were significantly lower and the apoptotic index was significantly higher than in rats given sodium chloride alone. Our findings suggest that limonene attenuates the gastric carcinogenesis enhanced by sodium chloride via increased apoptosis and decreased ODC activity in gastric cancers.

  6. Mucosal microbiome dysbiosis in gastric carcinogenesis.

    PubMed

    Coker, Olabisi Oluwabukola; Dai, Zhenwei; Nie, Yongzhan; Zhao, Guijun; Cao, Lei; Nakatsu, Geicho; Wu, William Kk; Wong, Sunny Hei; Chen, Zigui; Sung, Joseph J Y; Yu, Jun

    2017-08-01

    We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi'an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China. We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q<0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p<0.001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p<0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori-negative samples compared with H. pylori-positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis, D. pneumosintes, S. exigua, P. micra and S. anginosus in GC progression. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  7. Evaluation of anti-cancer and anti-oxidative potential of Syzygium Cumini against benzo[a]pyrene (BaP) induced gastric carcinogenesis in mice.

    PubMed

    Goyal, P K; Verma, Preeti; Sharma, Priyanka; Parmar, Jyoti; Agarwal, Annapurna

    2010-01-01

    Syzygium cummini extract (SCE) was used in the present study to explore anti-tumor promoting activity in a stomach carcinogenesis model in mice. For this purpose, Swiss albino mice were administered with 1 mg of benzo-a-pyrene (BaP) in 100?l sesame oil by oral gavage twice a week for 4 consecutive weeks. The animals were sacrificed 14 weeks after the last administration of BaP. Oral administration of the extract to pre-treated (i.e. SCE as 25mg/kg b. wt./ day before BaP application for 2 weeks), post-treated (i.e. SCE after BaP application for 8 weeks) and pre-post treated (i.e. SCE for 2 weeks before treatment of BaP followed by the concomitant treatment with SCE and BaP for 4 weeks during and 2 weeks after the last dose of BaP) groups provided a significant reduction in tumor incidence, tumor burden and cumulative number of gastric carcinomas along with a significant elevation of phase II detoxifying enzymes, and inhibition of lipid per oxidation in the stomach. Thus, the present data suggest that the Syzygium cummini extract has anti-tumor and anti-oxidative potential against chemical induced stomach carcinogenesis.

  8. Modulatory effect of naringenin on N-methyl-N'-nitro-N-nitrosoguanidine- and saturated sodium chloride-induced gastric carcinogenesis in male Wistar rats.

    PubMed

    Ganapathy, Ekambaram; Peramaiyan, Rajendran; Rajasekaran, Devaraja; Venkataraman, Magesh; Dhanapal, Sakthisekaran

    2008-10-01

    Naringenin is a flavanone that is believed to have many biological actions, including as an anti-oxidant, free radical scavenger and an antiproliferative agent. The global incidence of gastric carcinoma is increasing rapidly, more than for any other cancer. Therefore, in the present study, we tested the effects of naringenin on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and saturated sodium chloride (S-NaCl) in rats. Male Wistar rats were divided into five groups and treated over a period of 20 weeks as follows: (i) a control group given corn oil (1 mL/rat, p.o.) daily 20 weeks; (ii) 200 mg/kg, p.o., MNNG on Days 0 and 14 with S-NaCl (1 mL/rat) administered twice a week for the first 3 weeks; (iii) 200 mg/kg, p.o., MNNG on Days 0 and 14, with naringenin (200 mg/kg, p.o., daily) treatment for the entire 20 weeks; (iv) 200 mg/kg, p.o., MNNG on Days 0 and 14, with naringenin treatment (200 mg/kg, p.o., daily) initiated from 6 to 20 weeks; (v) 200 mg/kg, p.o., naringenin alone daily for 20 weeks. In Group II rats in which gastric cancer was inducted with MNNG and S-NaCl, there was a significant increase in hydrogen peroxide and lipid peroxidation levels, with decreases in reduced glutathione, oxidized glutathione, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase. In addition, in Group II rats with gastric cancer, there were significant increases in the activity of cytochrome P450, cytochrome b(5) and NADPH cytochrome c reductase, with concomitant decreases in the activity of the phase II enzymes glutathione S-transferase and UDP-glucuronosyl transferase. Naringenin treatment (Groups III and IV) restored enzyme activity to near control levels. These results indicate that naringenin has a chemopreventive action against MNNG-induced gastric carcinoma in experimental rats.

  9. Helicobacter pylori infection, gastrin and cyclooxygenase-2 in gastric carcinogenesis.

    PubMed

    Shao, Yun; Sun, Kun; Xu, Wei; Li, Xiao-Lin; Shen, Hong; Sun, Wei-Hao

    2014-09-28

    Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori (H. pylori) infection and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demonstrated that expression of cyclooxygenase-2 (COX-2) is elevated in gastric carcinomas and in their precursor lesions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.

  10. Experimental Gastric Carcinogenesis in Cebus apella Nonhuman Primates

    PubMed Central

    Silva, Tanielly Cristina Raiol; Andrade Junior, Edilson Ferreira; Rezende, Alexandre Pingarilho; Carneiro Muniz, José Augusto Pereira; Lacreta Junior, Antonio Carlos Cunha; Assumpção, Paulo Pimentel; Calcagno, Danielle Queiroz; Demachki, Samia; Rabenhorst, Silvia Helena Barem; Smith, Marília de Arruda Cardoso; Burbano, Rommel Rodriguez

    2011-01-01

    The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU). Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9th day though on the 14th day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940th day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the tolerability and

  11. Long non-coding RNA HOTAIR promotes carcinogenesis and invasion of gastric adenocarcinoma

    SciTech Connect

    Lee, Na Keum; Lee, Jung Hwa; Park, Chan Hyuk; Yu, Dayeon; Lee, Yong Chan; Cheong, Jae-Ho; Noh, Sung Hoon; Lee, Sang Kil

    2014-08-22

    Highlights: • HOTAIR expression was tested in fifty patients with gastric cancer. • Cell proliferation was measured after HOTAIR silencing in gastric cancer cell line. • siRNA–HOTAIR suppresses cell invasiveness and capacity of migration. • Knock down of HOTAR leads to decreased expression of EMT markers. • Inhibition of HOTAIR induces apoptosis and cell cycle arrest. - Abstract: Gastric cancer is one of the major causes of cancer death worldwide; however, the mechanism of carcinogenesis is complex and poorly understood. Long non-coding RNA HOTAIR (HOX transcript antisense RNA) recently emerged as a promoter of metastasis in various cancers including gastric cancer. Here we investigated the impact of HOTAIR on apoptosis, cell proliferation and cell cycle to dissect the carcinogenesis of gastric cancer. We examined the mechanism of invasion and metastasis and analyzed the clinical significance of HOTAIR. Downregulation of HOTAIR was confirmed by two different siRNAs. The expression of HOTAIR was significantly elevated in various gastric cancer cell lines and tissues compared to normal control. si-HOTAIR significantly reduced viability in MKN 28, MKN 74, and KATO III cells but not in AGS cells. si-HOTAIR induced apoptosis in KATO III cells. Lymphovascular invasion and lymph node metastasis were more common in the high level of HOTAIR group. si-HOTAIR significantly decreased invasiveness and migration. si-HOTAIR led to differential expression of epithelial to mesenchymal transition markers. We found that HOTAIR was involved in inhibition of apoptosis and promoted invasiveness, supporting a role for HOTAIR in carcinogenesis and progression of gastric cancer.

  12. PABPC1 exerts carcinogenesis in gastric carcinoma by targeting miR-34c.

    PubMed

    Zhu, Jie; Ding, Hao; Wang, Xiaohong; Lu, Qi

    2015-01-01

    As one of the common malignant tumors that threaten human health severely, gastric carcinoma is the second highest cause of cancer death and the fourth most common cancer globally. However, the mechanism underlying gastric cancer is still not fully understood. PABPC1 plays an important role in translation, control the rate of mRNA deadenylation and participates in mRNA decay, which is involved in carcinogenesis. Here in present study, we reported that PABPC1 is an oncogenic protein in gastric carcinoma. The results showed that PABPC1 is upregulated in gastric carcinoma tissues, and high PABPC1 expression predicts poor survival. PABPC1 regulates proliferation and transformation of gastric cancer cells in vitro and in vivo. PABPC1 knockdown induces apoptosis by upregulating pro-apoptotic proteins and downregulating anti-apoptotic proteins. In addition, miR-34c is a target of PABPC1, and miR-34c is critically essential for the function of PABPC1. In summary, PABPC1 exerts carcinogenesis and promotes growth and survival of gastric cancer cells by regulating miR-34c.

  13. Helicobacter pylori CagA and gastric carcinogenesis.

    PubMed

    Zheng, Ri-Nan; Li, Shu-Rong; Masahiro, Asaka

    2012-01-01

    This study aimed to demonstrate the tyrosine phosphorylation motif (TPM) and 3' region structure of the Helicobacter pylori CagA gene as well as its SHP-2 binding activity in AGS cells and relation to gastric carcinogenesis. Sixteen clinical isolate H. pylori strains from eight duodenal ulcer and eight gastric adenocarcinoma patients were studied for CagA repeat sequence EPIYA motifs, C-terminal structure, and western blot analysis of CagA protein expression, translocation, and SHP-2 binding in AGS cells. Except for strain 547, all strains from the gastric adenocarcinoma patients were positive for CagA by PCR and had three EPIYA copy motifs. Western blotting showed that all strains were positive for CagA protein expression (100%), CagA protein translocation (100%), and SHP-2 binding (100%). CagA protein expression was significantly higher in the gastric adenocarcinoma patients than in the duodenal ulcer patients (P=0.0023). CagA protein translocation and SHP-2 binding in the gastric adenocarcinoma patients were higher than those in the duodenal ulcer patients, but no significant differences were found between the two groups (P=0.59, P=0.21, respectively). The TPMs and 3' region structures of the H. pylori CagA gene in the duodenal ulcer and gastric adenocarcinoma patients have no significant differences.

  14. Differential network analysis reveals dysfunctional regulatory networks in gastric carcinogenesis.

    PubMed

    Cao, Mu-Shui; Liu, Bing-Ya; Dai, Wen-Tao; Zhou, Wei-Xin; Li, Yi-Xue; Li, Yuan-Yuan

    2015-01-01

    Gastric Carcinoma is one of the most common cancers in the world. A large number of differentially expressed genes have been identified as being associated with gastric cancer progression, however, little is known about the underlying regulatory mechanisms. To address this problem, we developed a differential networking approach that is characterized by including a nascent methodology, differential coexpression analysis (DCEA), and two novel quantitative methods for differential regulation analysis. We first applied DCEA to a gene expression dataset of gastric normal mucosa, adenoma and carcinoma samples to identify gene interconnection changes during cancer progression, based on which we inferred normal, adenoma, and carcinoma-specific gene regulation networks by using linear regression model. It was observed that cancer genes and drug targets were enriched in each network. To investigate the dynamic changes of gene regulation during carcinogenesis, we then designed two quantitative methods to prioritize differentially regulated genes (DRGs) and gene pairs or links (DRLs) between adjacent stages. It was found that known cancer genes and drug targets are significantly higher ranked. The top 4% normal vs. adenoma DRGs (36 genes) and top 6% adenoma vs. carcinoma DRGs (56 genes) proved to be worthy of further investigation to explore their association with gastric cancer. Out of the 16 DRGs involved in two top-10 DRG lists of normal vs. adenoma and adenoma vs. carcinoma comparisons, 15 have been reported to be gastric cancer or cancer related. Based on our inferred differential networking information and known signaling pathways, we generated testable hypotheses on the roles of GATA6, ESRRG and their signaling pathways in gastric carcinogenesis. Compared with established approaches which build genome-scale GRNs, or sub-networks around differentially expressed genes, the present one proved to be better at enriching cancer genes and drug targets, and prioritizing

  15. Differential network analysis reveals dysfunctional regulatory networks in gastric carcinogenesis

    PubMed Central

    Cao, Mu-Shui; Liu, Bing-Ya; Dai, Wen-Tao; Zhou, Wei-Xin; Li, Yi-Xue; Li, Yuan-Yuan

    2015-01-01

    Gastric Carcinoma is one of the most common cancers in the world. A large number of differentially expressed genes have been identified as being associated with gastric cancer progression, however, little is known about the underlying regulatory mechanisms. To address this problem, we developed a differential networking approach that is characterized by including a nascent methodology, differential coexpression analysis (DCEA), and two novel quantitative methods for differential regulation analysis. We first applied DCEA to a gene expression dataset of gastric normal mucosa, adenoma and carcinoma samples to identify gene interconnection changes during cancer progression, based on which we inferred normal, adenoma, and carcinoma-specific gene regulation networks by using linear regression model. It was observed that cancer genes and drug targets were enriched in each network. To investigate the dynamic changes of gene regulation during carcinogenesis, we then designed two quantitative methods to prioritize differentially regulated genes (DRGs) and gene pairs or links (DRLs) between adjacent stages. It was found that known cancer genes and drug targets are significantly higher ranked. The top 4% normal vs. adenoma DRGs (36 genes) and top 6% adenoma vs. carcinoma DRGs (56 genes) proved to be worthy of further investigation to explore their association with gastric cancer. Out of the 16 DRGs involved in two top-10 DRG lists of normal vs. adenoma and adenoma vs. carcinoma comparisons, 15 have been reported to be gastric cancer or cancer related. Based on our inferred differential networking information and known signaling pathways, we generated testable hypotheses on the roles of GATA6, ESRRG and their signaling pathways in gastric carcinogenesis. Compared with established approaches which build genome-scale GRNs, or sub-networks around differentially expressed genes, the present one proved to be better at enriching cancer genes and drug targets, and prioritizing

  16. The Gastric Microbiome and Its Influence on Gastric Carcinogenesis: Current Knowledge and Ongoing Research.

    PubMed

    Zhang, Chao; Powell, Sarah Ellen; Betel, Doron; Shah, Manish A

    2017-06-01

    Gastric malignancies are a leading cause of cancer-related death worldwide. At least 2 microbial species are currently linked to carcinogenesis and the development of cancer within the human stomach. These include the bacterium Helicobacter pylori and the Epstein-Barr virus. In recent years, there has been increasing evidence that within the human gastrointestinal tract it is not only pathogenic microbes that impact human health but also the corresponding autochthonous microbial communities. This article reviews the gastrointestinal microbiome as it relates primarily to mechanisms of disease and carcinogenesis within the upper gastrointestinal tract. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Alterations in Gastric Microbiota After H. Pylori Eradication and in Different Histological Stages of Gastric Carcinogenesis

    PubMed Central

    Li, Tung Hiu; Qin, Youwen; Sham, Pak Chung; Lau, K.S.; Chu, Kent-Man; Leung, Wai K.

    2017-01-01

    The role of bacteria other than Helicobacter pylori (HP) in the stomach remains elusive. We characterized the gastric microbiota in individuals with different histological stages of gastric carcinogenesis and after receiving HP eradication therapy. Endoscopic gastric biopsies were obtained from subjects with HP gastritis, gastric intestinal metaplasia (IM), gastric cancer (GC) and HP negative controls. Gastric microbiota was characterized by Illumina MiSeq platform targeting the 16 S rDNA. Apart from dominant H. pylori, we observed other Proteobacteria including Haemophilus, Serratia, Neisseria and Stenotrophomonas as the major components of the human gastric microbiota. Although samples were largely converged according to the relative abundance of HP, a clear separation of GC and other samples was recovered. Whilst there was a strong inverse association between HP relative abundance and bacterial diversity, this association was weak in GC samples which tended to have lower bacterial diversity compared with other samples with similar HP levels. Eradication of HP resulted in an increase in bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to individuals without HP. In conclusion, HP colonization results in alterations of gastric microbiota and reduction in bacterial diversity, which could be restored by antibiotic treatment. PMID:28322295

  18. Alterations in Gastric Microbiota After H. Pylori Eradication and in Different Histological Stages of Gastric Carcinogenesis.

    PubMed

    Li, Tung Hiu; Qin, Youwen; Sham, Pak Chung; Lau, K S; Chu, Kent-Man; Leung, Wai K

    2017-03-21

    The role of bacteria other than Helicobacter pylori (HP) in the stomach remains elusive. We characterized the gastric microbiota in individuals with different histological stages of gastric carcinogenesis and after receiving HP eradication therapy. Endoscopic gastric biopsies were obtained from subjects with HP gastritis, gastric intestinal metaplasia (IM), gastric cancer (GC) and HP negative controls. Gastric microbiota was characterized by Illumina MiSeq platform targeting the 16 S rDNA. Apart from dominant H. pylori, we observed other Proteobacteria including Haemophilus, Serratia, Neisseria and Stenotrophomonas as the major components of the human gastric microbiota. Although samples were largely converged according to the relative abundance of HP, a clear separation of GC and other samples was recovered. Whilst there was a strong inverse association between HP relative abundance and bacterial diversity, this association was weak in GC samples which tended to have lower bacterial diversity compared with other samples with similar HP levels. Eradication of HP resulted in an increase in bacterial diversity and restoration of the relative abundance of other bacteria to levels similar to individuals without HP. In conclusion, HP colonization results in alterations of gastric microbiota and reduction in bacterial diversity, which could be restored by antibiotic treatment.

  19. Gastric microbiota and carcinogenesis: the role of non-Helicobacter pylori bacteria - A systematic review.

    PubMed

    Dias-Jácome, Emanuel; Libânio, Diogo; Borges-Canha, Marta; Galaghar, Ana; Pimentel-Nunes, Pedro

    2016-09-01

    Helicobacter pylori is the strongest risk factor for gastric cancer. However, recent advances in DNA sequencing technology have revealed a complex microbial community in the stomach that could also contribute to the development of gastric cancer. The aim of this study was to present recent scientific evidence regarding the role of non-Helicobacter pylori bacteria in gastric carcinogenesis. A systematic review of original articles published in PubMed in the last ten years related to gastric microbiota and gastric cancer in humans was performed. Thirteen original articles were included. The constitution of gastric microbiota appears to be significantly affected by gastric cancer and premalignant lesions. In fact, differences in gastric microbiota have been documented, depending on Helicobacter pylori status and gastric conditions, such as non-atrophic gastritis, intestinal metaplasia and cancer. Gastric carcinogenesis can be associated with an increase in many bacteria (such as Lactobacillus coleohominis, Klebsiella pneumoniae or Acinetobacter baumannii) as well as decrease in others (such as Porphyromonas spp, Neisseria spp, Prevotella pallens or Streptococcus sinensis). However, there is no conclusive data that confirms if these changes in microbiota are a cause or consequence of the process of carcinogenesis. Even though there is limited evidence in humans, microbiota differences between normal individuals, pre-malignant lesions and gastric cancer could suggest a progressive shift in the constitution of gastric microbiota in carcinogenesis, possibly resulting from a complex cross-talk between gastric microbiota and Helicobacter pylori. However, further studies are needed to elucidate the specific role (if any) of different microorganisms.

  20. Factors that modify radiation-induced carcinogenesis.

    PubMed

    Kennedy, Ann R

    2009-11-01

    It is known that numerous factors can influence radiation carcinogenesis in animals; these factors include the specific characteristics of the radiation (radiation type and dose, dose-rate, dose-fractionation, dose distribution, etc.) as well as many other contributing elements that are not specific to the radiation exposure, such as animal genetic characteristics and age, the environment of the animal, dietary factors and whether specific modifying agents for radiation carcinogenesis have been utilized in the studies. This overview focuses on the modifying factors for radiation carcinogenesis, in both in vivo and in vitro systems, and includes a discussion of agents that enhance (e.g., promoting agents) or suppress (e.g., cancer preventive agents) radiation-induced carcinogenesis. The agents that enhance or suppress radiation carcinogenesis in experimental model systems have been shown to lead to effects equally as large as other known modifying factors for radiation-induced carcinogenesis (e.g., dose-rate, dose-fractionation, linear energy transfer). It is known that dietary factors play an important role in determining the yields of radiation-induced cancers in animal model systems, and it is likely that they also influence radiation-induced cancer risks in human populations.

  1. Prevention of spontaneous and chemically induced carcinogenesis using activated carbon fiber adsorbent. II. Inhibitory effect of the activated carbon fiber adsorbent 'Aqualen' on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats.

    PubMed

    Anisimov, V N; Zabezhinski, M A; Popovich, I G; Lieberman, A I; Shmidt, J L

    1999-04-26

    Two-month-old female LIO rats were given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) with tap water in a concentration of 100 mg/l for 12 months (groups 1 and 2) or were kept without the carcinogen treatment (groups 3 and 4). From the first day of exposure to MNNG rats from groups 2 and 3 were given activated carbon fiber adsorbent Aqualen in their diet five times per week together with lab chow in a daily dose of 100 mg/kg of body weight. The experiment was finalized 16 months after first exposure to the carcinogen. The total stomach adenocarcinoma incidence was 43% in group 1 and 39% in group 2, whereas invasive stomach adenocarcinomas occurred in 36% and 8% of rats from groups 1 and 2, respectively (P < 0.05). Tumors other then stomach sites (duodenum and liver) only developed in rats from group 1 (29%). No lesions were observed in rats exposed to Aqualen without MNNG. Thus, our results demonstrate the inhibitory effect of the activated carbon fiber adsorbent Aqualen on stomach carcinogenesis in rats.

  2. Metabolomic analysis reveals altered metabolic pathways in a rat model of gastric carcinogenesis

    PubMed Central

    Gu, Jinping; Hu, Xiaomin; Shao, Wei; Ji, Tianhai; Yang, Wensheng; Zhuo, Huiqin; Jin, Zeyu; Huang, Huiying; Chen, Jiacheng; Huang, Caihua; Lin, Donghai

    2016-01-01

    Gastric cancer (GC) is one of the most malignant tumors with a poor prognosis. Alterations in metabolic pathways are inextricably linked to GC progression. However, the underlying molecular mechanisms remain elusive. We performed NMR-based metabolomic analysis of sera derived from a rat model of gastric carcinogenesis, revealed significantly altered metabolic pathways correlated with the progression of gastric carcinogenesis. Rats were histologically classified into four pathological groups (gastritis, GS; low-grade gastric dysplasia, LGD; high-grade gastric dysplasia, HGD; GC) and the normal control group (CON). The metabolic profiles of the five groups were clearly distinguished from each other. Furthermore, significant inter-metabolite correlations were extracted and used to reconstruct perturbed metabolic networks associated with the four pathological stages compared with the normal stage. Then, significantly altered metabolic pathways were identified by pathway analysis. Our results showed that oxidative stress-related metabolic pathways, choline phosphorylation and fatty acid degradation were continually disturbed during gastric carcinogenesis. Moreover, amino acid metabolism was perturbed dramatically in gastric dysplasia and GC. The GC stage showed more changed metabolite levels and more altered metabolic pathways. Two activated pathways (glycolysis; glycine, serine and threonine metabolism) substantially contributed to the metabolic alterations in GC. These results lay the basis for addressing the molecular mechanisms underlying gastric carcinogenesis and extend our understanding of GC progression. PMID:27527852

  3. Effect of S-allylcysteine on oxidant-antioxidant status during N-methyl-N'-nitro-N-nitrosoguanidine and saturated sodium chloride-induced gastric carcinogenesis in Wistar rats.

    PubMed

    Velmurugan, Balaiya; Bhuvaneswari, Vaidhyanathan; Nagini, Siddavaram

    2003-01-01

    We investigated the chemopreventive effect of S-allylcysteine (SAC), a water-soluble garlic constituent against gastric carcinogenesis induced in male Wistar rats by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and saturated sodium chloride (S-NaCl). The animals were divided into four groups of six animals. Rats in groups 1 and 2 were administered MNNG (200 mg/kg body weight) on days 0 and 14 as well as S-NaCl (1 mL/rat) three days during weeks 0 to 3, and thereafter placed on basal diet until the end of the experiment. Rats in group 2 in addition received SAC (200 mg/kg body weight) three times per week starting on the day following the first exposure to MNNG and continued until the end of the experimental period. Group 3 animals were given SAC alone as in group 2. Group 4 animals received basal diet and tap water throughout the experiment and served as the untreated control. The animals were sacrificed after an experimental period of 21 weeks. Measurement of lipid peroxidation and antioxidants of the glutathione redox cycle in the stomach tissue, liver and venous blood was used to monitor the chemopreventive potential of SAC. All animals that received MNNG and S-NaCl alone, developed tumours, identified histologically as squamous cell carcinomas. In the tumour tissue, diminished lipid peroxidation was accompanied by increase in reduced glutathione (GSH) and GSH-dependent enzymes, whereas in the liver and circulation, enhanced lipid peroxidation was associated with antioxidant depletion. Administration of SAC suppressed the incidence of MNNG+S-NaCl-induced gastric tumours as revealed by the absence of carcinomas. SAC ameliorated MNNG-induced decreased susceptibility of the gastric mucosa to lipid peroxidation, whilst simultaneously increasing the antioxidant status. In the liver and blood, SAC reduced the extent of lipid peroxidation and significantly enhanced antioxidant activities. We suggest that SAC exerts its chemopreventive effects by modulating lipid

  4. The Role of PPARγ in Helicobacter pylori Infection and Gastric Carcinogenesis

    PubMed Central

    Lee, Jong-Min; Kim, Sung Soo; Cho, Young-Seok

    2012-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPARγ plays an important role in gastric mucosal injury due to Helicobacter pylori (H. pylori). As H. pylori infection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPARγ in H. pylori infection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPARγ in H. pylori infection and its related gastric carcinogenesis. PMID:22936949

  5. Gastric Carcinogenesis in the miR-222/221 Transgenic Mouse Model

    PubMed Central

    Choi, Boram; Yu, Jieun; Han, Tae-Su; Kim, Young-Kook; Hur, Keun; Kang, Byeong-Cheol; Kim, Woo-Ho; Kim, Dae-Yong; Lee, Hyuk-Joon; Kim, V. Narry; Yang, Han-Kwang

    2017-01-01

    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. PMID:27338035

  6. The chronological sequence of somatic mutations in early gastric carcinogenesis inferred from multiregion sequencing of gastric adenomas

    PubMed Central

    Lim, Chul-Hyun; Cho, Yu Kyung; Kim, Sang Woo; Choi, Myung-Gyu; Rhee, Je-Keun; Chung, Yeun-Jun; Lee, Sug-Hyung; Kim, Tae-Min

    2016-01-01

    Mutation profiles and intratumoral heterogeneity are not well understood for benign gastric adenomas, some of which progress into malignant gastric adenocarcinomas. In this study, we performed whole-exome sequencing of three microsatellite stable (MSS) and two microsatellite instability-high (MSI-H) gastric adenomas with three regional tumor biopsies per case. We observed that the mutation abundance of benign gastric adenomas was comparable to those of gastric adenocarcinomas, suggesting that the mutational makeup for gastric carcinogenesis may already be achieved in benign adenomas. The extent of intratumoral heterogeneity was more substantial for MSS genomes in that only 1% - 14% of somatic mutations were common across the regional biopsies or ‘public’, while 50% - 94% of mutations were public in MSI-H gastric adenomas. We observed biallelic, loss-of-functional events of APC with truncating mutations and/or 5q losses for all cases, mostly as public events. All MSS gastric adenomas also harbored ARID2 truncating mutations, often as multiple, region-specific ones indicative of convergent evolution. Hotspot missense mutations on known cancer genes such as ERBB2 and KRAS were largely observed as region-specific aberrations. These findings suggest that biallelic functional APC inactivation initiates the gastric carcinogenesis and is followed by mutations of histone modifiers and then activation of known cancer-related genes. As the first exome-wide multi-region mutational profiling of gastric adenomas, our study provides clues on the chronological sequence of somatic mutations and their clonal architectures in early gastric carcinogenesis. PMID:27175599

  7. The Role of microRNAs in Helicobacter pylori Pathogenesis and Gastric Carcinogenesis

    PubMed Central

    Noto, Jennifer M.; Peek, Richard M.

    2012-01-01

    Gastric carcinogenesis is a multistep process orchestrated by aberrancies in the genetic and epigenetic regulation of oncogenes and tumor suppressor genes. Chronic infection with Helicobacter pylori is the strongest known risk factor for the development of gastric cancer. H. pylori expresses a spectrum of virulence factors that dysregulate host intracellular signaling pathways that lower the threshold for neoplastic transformation. In addition to bacterial determinants, numerous host and environmental factors increase the risk of gastric carcinogenesis. Recent discoveries have shed new light on the involvement of microRNAs (miRNAs) in gastric carcinogenesis. miRNAs represent an abundant class of small, non-coding RNAs involved in global post-transcriptional regulation and, consequently, play an integral role at multiple steps in carcinogenesis, including cell cycle progression, proliferation, apoptosis, invasion, and metastasis. Expression levels of miRNAs are frequently altered in malignancies, where they function as either oncogenic miRNAs or tumor suppressor miRNAs. This review focuses on miRNAs dysregulated by H. pylori and potential etiologic roles they play in H. pylori-mediated gastric carcinogenesis. PMID:22919587

  8. Study of chemical and radiation induced carcinogenesis

    SciTech Connect

    Chmura, A.

    1995-11-01

    The study of chemical and radiation induced carcinogenesis has up to now based many of its results on the detection of genetic aberrations using the fluorescent in situ hybridization (FISH) technique. FISH is time consuming and this tends to hinder its use for looking at large numbers of samples. We are currently developing new technological advances which will increase the speed, clarity and functionality of the FISH technique. These advances include multi-labeled probes, amplification techniques, and separation techniques.

  9. Helicobacter pylori Is Associated with miR-133a Expression through Promoter Methylation in Gastric Carcinogenesis.

    PubMed

    Lim, Joo Hyun; Kim, Sang Gyun; Choi, Ji Min; Yang, Hyo-Joon; Kim, Joo Sung; Jung, Hyun Chae

    2017-09-28

    To investigate whether Helicobacter pylori eradication can reverse epigenetic silencing of microRNAs (miRNAs) which are associated with H. pylori-induced gastric carcinogenesis. We examined expression and promoter methylation of miR-34b/c, miR-133a, let-7a, and let-7i in gastric cancer cell line, before/after demethylation. Among them, epigenetically controlled miRNAs were identified. Their expression and promoter methylation was examined in human tissues of H. pylori-positive gastric cancer (T), H. pylori-positive gastritis (H), and H. pylori-negative controls (C). We also compared changes of miRNA expression and promoter methylation in H. pylori-positive patients who were endoscopically treated for early gastric cancer, between baseline and 1 year later according to eradication status. In gastric cancer cell line, miR-34b/c, and miR-133a showed epigenetic silencing. In human tissues, miR-34b/c and miR-133a showed serial increase of promoter methylation in order of C, H, and T (all, p〈0.01), and the miR-133a expression showed serial decrease (C vs H, p=0.02; H vs T, p=0.01; C vs T, p〈0.01) while miR-34b and miR-34c expressions did not. H. pylori eradication induced decrease of methylation (p〈0.01) and increase of miR-133a expression (p=0.03), compared with noneradication group. This result suggests H. pylori eradication could reverse methylation-silencing of miR-133a which is involved in H. pylori-induced gastric carcinogenesis.

  10. Latest insights into the effects of Helicobacter pylori infection on gastric carcinogenesis

    PubMed Central

    Murakami, Kazunari; Kodama, Masaaki; Fujioka, Toshio

    2006-01-01

    There appears to be the strong association between Helicobacter pylori (H pylori) and gastric cancer. We reviewed the latest evidences about the effects of H pylori infection on gastric carcinogenesis, classified into epidemiology, dynamics of gastric mucosal changes, DNA damages, virulence factors, host factors, and source of gastric malignancy. Through the considerable progress made in research into virulence factors resulting from differences between H pylori strains, such as cagA positivity, as well as into host factors, such as gene polymorphisms, a diverse spectrum of H pylori-associated diseases, including gastric cancer, is beginning to lend itself to elucidation. The impact of the novel hypothesis advanced by Houghton et al proposing bone-marrow derived stem cells (BMDC) as a potential source of gastric malignancy on evolving research remains to be seen with interest. Further progress in research into H pylori eradication as a viable prophylaxis of gastric cancer, as well as into the mechanisms of gastric carcinogenesis, is to be eagerly awaited for the current year and beyond. PMID:16718758

  11. Role of Helicobacter pylori infection in gastric carcinogenesis: Current knowledge and future directions

    PubMed Central

    Sokic-Milutinovic, Aleksandra; Alempijevic, Tamara; Milosavljevic, Tomica

    2015-01-01

    Helicobacter pylori (H. pylori) plays a role in the pathogenesis of gastric cancer. The outcome of the infection depends on environmental factors and bacterial and host characteristics. Gastric carcinogenesis is a multistep process that is reversible in the early phase of mucosal damage, but the exact point of no return has not been identified. Therefore, two main therapeutic strategies could reduce gastric cancer incidence: (1) eradication of the already present infection; and (2) immunization (prior to or during the course of the infection). The success of a gastric cancer prevention strategy depends on timing because the prevention strategy must be introduced before the point of no return in gastric carcinogenesis. Although the exact point of no return has not been identified, infection should be eradicated before severe atrophy of the gastric mucosa develops. Eradication therapy rates remain suboptimal due to increasing H. pylori resistance to antibiotics and patient noncompliance. Vaccination against H. pylori would reduce the cost of eradication therapies and lower gastric cancer incidence. A vaccine against H. pylori is still a research challenge. An effective vaccine should have an adequate route of delivery, appropriate bacterial antigens and effective and safe adjuvants. Future research should focus on the development of rescue eradication therapy protocols until an efficacious vaccine against the bacterium becomes available. PMID:26556993

  12. Critical pathogenic steps to high risk Helicobacter pylori gastritis and gastric carcinogenesis

    PubMed Central

    Lee, Inchul

    2014-01-01

    Helicobacter pylori (H. pylori) gastritis may progress to high risk gastropathy and cancer. However, the pathological progression has not been characterized in detail. H. pylori induce persistent inflammatory infiltration. Neutrophils are unique in that they directly infiltrate into foveolar epithelium aiming the proliferative zone specifically. Neutrophilic proliferative zone foveolitis is a critical pathogenic step in H. pylori gastritis inducing intensive epithelial damage. Epithelial cells carrying accumulated genomic damage and mutations show the Malgun (clear) cell change, characterized by large clear nucleus and prominent nucleolus. Malgun cells further undergo atypical changes, showing nuclear folding, coarse chromatin, and multiple nucleoli. The atypical Malgun cell (AMC) change is a novel premalignant condition in high risk gastropathy, which may progress and undergo malignant transformation directly. The pathobiological significance of AMC in gastric carcinogenesis is reviewed. A new diagnosis system of gastritis is proposed based on the critical pathologic steps classifying low and high risk gastritis for separate treatment modality. It is suggested that the regulation of H. pylori-induced neutrophilic foveolitis might be a future therapeutic goal replacing bactericidal antibiotics approach. PMID:24914362

  13. Critical pathogenic steps to high risk Helicobacter pylori gastritis and gastric carcinogenesis.

    PubMed

    Lee, Inchul

    2014-06-07

    Helicobacter pylori (H. pylori) gastritis may progress to high risk gastropathy and cancer. However, the pathological progression has not been characterized in detail. H. pylori induce persistent inflammatory infiltration. Neutrophils are unique in that they directly infiltrate into foveolar epithelium aiming the proliferative zone specifically. Neutrophilic proliferative zone foveolitis is a critical pathogenic step in H. pylori gastritis inducing intensive epithelial damage. Epithelial cells carrying accumulated genomic damage and mutations show the Malgun (clear) cell change, characterized by large clear nucleus and prominent nucleolus. Malgun cells further undergo atypical changes, showing nuclear folding, coarse chromatin, and multiple nucleoli. The atypical Malgun cell (AMC) change is a novel premalignant condition in high risk gastropathy, which may progress and undergo malignant transformation directly. The pathobiological significance of AMC in gastric carcinogenesis is reviewed. A new diagnosis system of gastritis is proposed based on the critical pathologic steps classifying low and high risk gastritis for separate treatment modality. It is suggested that the regulation of H. pylori-induced neutrophilic foveolitis might be a future therapeutic goal replacing bactericidal antibiotics approach.

  14. Alterations of the TP53 Gene in Gastric and Esophageal Carcinogenesis

    PubMed Central

    Bellini, Marilanda Ferreira; Cadamuro, Aline Cristina Targa; Succi, Maysa; Proença, Marcela Alcântara; Silva, Ana Elizabete

    2012-01-01

    TP53 genes is one of more important tumor suppressor gene, which acts as a potent transcription factor with fundamental role in the maintenance of genetic stability. The development of esophageal and gastric cancers is a multistep process resulting in successive accumulation of genetic alterations that culminates in the malignant transformation. Thus, this study highlights the participation of the main genetic alterations of the TP53 gene in esophageal and gastric carcinogenesis. Among these changes, high frequency of TP53 mutations, loss of heterozygosity (LOH), overexpression of the p53 protein, and consequently loss of p53 function, which would be early events in esophageal and gastric cancers, as well as an important biomarker of the prognosis and treatment response. Furthermore, Single Nucleotide Polymorphisms (SNPs) of TP53 have been implicated in the development and prognosis of several cancers, mainly TP53 codon 72 polymorphism whose role has been extensively studied in relation to susceptibility for esophageal and gastric cancer development. PMID:22919278

  15. [Mechanisms of asbestos-induced carcinogenesis].

    PubMed

    Toyokuni, Shinya; Jiang, Li; Hu, Qian; Nagai, Hirotaka; Okazaki, Yasumasa; Akatsuka, Shinya; Yamashita, Yoriko

    2011-05-01

    Several types of fibrous stone called asbestos have been an unexpected cause of human cancer in the history. This form of mineral is considered precious in that they are heat-, friction-, and acid-resistant, are obtained easily from mines, and can be modified to any form with many industrial merits. However, it became evident that the inspiration of asbestos causes a rare cancer called malignant mesothelioma. Because of the long incubation period, the peak year for malignant mesothelioma is expected to be 2025 in Japan. Thus, it is necessary to elucidate the mechanisms of asbestos-induced mesothelial carcinogenesis. In this review, we summarize the cutting edge results of our 5-year project funded by a MEXT grant, in which local iron deposition and the characteristics of mesothelial cells are the key issues.

  16. Relatedness of Helicobacter pylori populations to gastric carcinogenesis

    PubMed Central

    Dong, Quan-Jiang; Zhan, Shu-Hui; Wang, Li-Li; Xin, Yong-Ning; Jiang, Man; Xuan, Shi-Ying

    2012-01-01

    Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects half of the human population. The infection is associated with chronic inflammation of the gastric mucosa and peptic ulcers. It is also a major risk factor for gastric cancer. Phylogenetic analysis of global strains reveals there are seven populations of H. pylori, including hpAfrica1, hpAfrica2, hpEastAsia, hpEurope, hpNEAfrica, hpAsia2 and hpSahul. These populations are consistent with their geographical origins, and possibly result from geographical separation of the bacterium leading to reduced bacterial recombination in some populations. For each population, H. pylori has evolved to possess genomic contents distinguishable from others. The hpEurope population is distinct in that it has the largest genome of 1.65 mbp on average, and the highest number of coding sequences. This confers its competitive advantage over other populations but at the cost of a lower infection rate. The large genomic size could be a cause of the frequent occurrence of the deletion of the cag pathogenicity island in H. pylori strains from hpEurope. The incidence of gastric cancer varies among different geographical regions. This can be attributed in part to different rates of infection of H. pylori. Recent studies found that different populations of H. pylori vary in their carcinogenic potential and contribute to the variation in incidence of gastric cancer among geographical regions. This could be related to the ancestral origin of H. pylori. Further studies are indicated to investigate the bacterial factors contributing to differential virulence and their influence on the clinical features in infected individuals. PMID:23236231

  17. Carcinogenesis, prevention and early detection of gastric cancer: where we are and where we should go.

    PubMed

    González, Carlos A; Agudo, Antonio

    2012-02-15

    Helicobacter pylori is the most common cause of gastric cancer (GC), though smoking, alcohol, diet, genetics and epigenetic factors may also have a role in the occurrence of the disease. Why H. pylori cause GC in only a minority of those infected remains unknown. Although mechanisms of H. pylori-induced carcinogenesis are not yet well understood, several genotypes of H. pylori have been associated with strain virulence and disease risk. Primary prevention of GC should be addressed by avoiding exposure to factors that increase the risk and to promote factors associated with decrease risk. Vaccines against H. pylori are an ongoing promise and not yet available. Chemoprevention through vitamin supplementation has shown no benefit. Screening and eradication of H. pylori in the general population is not advised. Given that GC is a multiple-steps process, the identification of patients with preneoplastic lesions with high risk of progression, and periodic endoscopic surveillance of them represents the most effective way for early diagnosis of GC. However, clinical guidelines for surveillance are lacking and there are no clear criteria to classify patients into high or low risk of progressing to GC. No study has shown the potential usefulness of combining the information on the type of preneoplastic lesions, genetic and epigenetic, lifestyle and virulence bacterial factors in order to identify high risk patients who need more intensive surveillance. The integration of all this information, in a prediction model requires further research and could be the most important contribution for reducing the burden of GC.

  18. Telomere length in the gastric mucosa after Helicobacter pylori eradication and its potential role in the gastric carcinogenesis.

    PubMed

    Tahara, Tomomitsu; Tahara, Sayumi; Tuskamoto, Tetsuya; Horiguchi, Noriyuki; Kawamura, Tomohiko; Okubo, Masaaki; Ishizuka, Takamitsu; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Shibata, Tomoyuki; Kuroda, Makoto; Ohmiya, Naoki

    2017-02-14

    The molecular mechanisms of gastric carcinogenesis after Helicobacter pylori (H. pylori) eradication remain unclear. We examined the telomere length of gastric mucosa samples after successful H. pylori eradication in patients without and those with gastric cancer. Telomere length was measured by the real-time PCR among four different groups of biopsies: gastric body from subjects without history of H. pylori infection (Hp-: n = 23), gastric body from cancer-free subjects after H. pylori eradication (cancer-free body: n = 24), gastric body from early gastric cancer patients diagnosed after H. pylori eradication (EGC body: n = 35) and its paired samples from adjacent mucosa of cancerous area (EGC ADJ: n = 35). The Hp-group presented the longest telomeres among the all groups (Hp- vs. all others, all P < 0.05). Samples from EGC body group showed shorter telomere length than the samples from cancer-free body groups (P < 0.05). Conversely, samples from EGC ADJ group showed rather longer telomere length compared to the EGC body group (P < 0.05), which was also confirmed by the comparison of 35 matched samples (P = 0.0007). Among the samples after H. pylori eradication, shorter telomere length was associated with higher expression of IL-1B and NF-kB (P < 0.0001, 0.0006, respectively). Longer telomere length was also associated with higher expression of TNF-A (P = 0.01). Telomere shortening seems to be important initial steps in gastric cancer predisposition after H. pylori eradication, while it might shift to lengthening to acquire more aggressive pathway to develop cancer.

  19. Analysis of Gastric Body Microbiota by Pyrosequencing: Possible Role of Bacteria Other Than Helicobacter pylori in the Gastric Carcinogenesis.

    PubMed

    Sohn, Sung-Hwa; Kim, Nayoung; Jo, Hyun Jin; Kim, Jaeyeon; Park, Ji Hyun; Nam, Ryoung Hee; Seok, Yeong-Jae; Kim, Yeon-Ran; Lee, Dong Ho

    2017-06-01

    Gastric microbiota along with Helicobacter pylori (HP) plays a key role in gastric disease. The aim of our study is to investigate the difference of human gastric microbiota between antrum and body according to disease (control vs. gastric cancer) and HP status. Each antrum and body biopsy was collected from 12 subjects at Seoul National University Bundang Hospital. Gastric microbiota was analyzed by bar-coded 454 pyrosequencing of the 16S rRNA gene. Twelve subjects consisted of HP-negative control (n = 2), HP-negative cancer (n = 2), HP-positive control (n = 3), and HP-positive cancer (n = 5). The analysis was focused on non-HP urease-producing bacteria (UB) and non-HP nitrosating or nitroreducing bacteria (NB) between antrum and body. Gastric body samples showed higher diversity compared to gastric antrum mucosa samples but there was no significant difference. The mean of operational taxonomic units was higher in HP(-) cancer than HP(+) cancer (antrum, 273.5 vs. 228.2, P = 0.439; body, 585.5 vs. 183.2, P = 0.053). The number of non-HP UB and non-HP NB was higher in HP(-) cancer groups than the others. These differences were more pronounced in the body (P = 0.051 and P = 0.081, respectively). Analysis of overlap of non-HP UB and non-HP NB revealed the higher composition of Streptococcus pseudopneumoniae, S. parasanguinis, and S. oralis in HP(-) cancer groups than the others, only in the body (P = 0.030) but not in the antrum (P = 0.123). Higher diversity and higher composition of S. pseudopneumoniae, S. parasanguinis, and S. oralis in HP(-) cancer group than the other groups in the body suggest that analysis of microbiota from body mucosa could be beneficial to identify a role of non-HP bacteria in the gastric carcinogenesis.

  20. Causes and consequences of microsatellite instability in gastric carcinogenesis

    PubMed Central

    Velho, Sérgia; Fernandes, Maria Sofia; Leite, Marina; Figueiredo, Ceu; Seruca, Raquel

    2014-01-01

    Loss of DNA mismatch repair (MMR) function, due to somatic or germline epi/genetic alterations of MMR genes leads to the accumulation of numerous mutations across the genome, creating a molecular phenotype known as microsatellite instability (MSI). In gastric cancer (GC), MSI occurs in about 15% to 30% of the cases. This review summarizes the current knowledge on the molecular mechanisms underlying the acquisition of MSI in GC as well as on the clinic, pathologic and molecular consequences of the MSI phenotype. Additionally, current therapeutic strategies for GC and their applicability in the MSI subset are also discussed. PMID:25469011

  1. Analysis of Gastric Microbiota by Pyrosequencing: Minor Role of Bacteria Other Than Helicobacter pylori in the Gastric Carcinogenesis.

    PubMed

    Jo, Hyun Jin; Kim, Jaeyeon; Kim, Nayoung; Park, Ji Hyun; Nam, Ryoung Hee; Seok, Yeong-Jae; Kim, Yeon-Ran; Kim, Joo Sung; Kim, Jung Mogg; Kim, Jung Min; Lee, Dong Ho; Jung, Hyun Chae

    2016-10-01

    Little is known about the role of gastric microbiota except for Helicobacter pylori (HP) in human health and disease. We compared the differences of human gastric microbiota according to gastric cancer or control and HP infection status and assessed the role of bacteria other than HP. Gastric microbiota of 63 antral mucosal and 18 corpus mucosal samples were analyzed by bar-coded 454 pyrosequencing of the 16S rRNA gene. Antral samples were divided into four subgroups based on HP positivity in pyrosequencing and the presence of cancer. The analysis was focused on bacteria other than HP, especially nitrosating or nitrate-reducing bacteria (NB). The changes of NB in antral mucosa of 16 subjects were followed up. The number of NB other than HP (non-HP-NB) was two times higher in the cancer groups than in the control groups, but it did not reach statistical significance. The number of non-HP-NB tends to increase over time, but this phenomenon was prevented by HP eradication in the HP-positive control group, but not in the HP-positive cancer group. We could not find the significant role of bacteria other than HP in the gastric carcinogenesis. © 2016 John Wiley & Sons Ltd.

  2. p53, a potential predictor of Helicobacter pylori infection-associated gastric carcinogenesis?

    PubMed Central

    Lu, Nong-Hua

    2016-01-01

    Helicobacter pylori (H. pylori) is an ancient and persistent inhabitant of the human stomach that is closely linked to the development of gastric cancer (GC). . Emerging evidence suggests that H. pylori strain interactions with gastric epithelial cells subvert the best- characterized p53 tumour suppressor pathway. A high prevalence of p53 mutations is related to H. pylori infection. H. pylori also accelerates p53 protein degradation by disturbing the MDM2-P53 feedback loop. Additionally, H. pylori triggers the alteration of other p53 isoforms. Dysregulation of p53 by H. pylori infection contributes to gastric carcinogenesis by mediating cell proliferation and apoptosis. This review focuses on the regulation of p53 in H. pylori infection-associated GC. PMID:27556187

  3. Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer

    PubMed Central

    Zhao, Xiaodong; Bao, Liming; Huang, Daochao; Song, Lihua; Li, Yang

    2016-01-01

    Aberrant STAT3 activation occurs in most human gastric cancers (GCs) and contributes to the malignant progression of GC, but mechanism(s) underlying aberrant STAT3 remain largely unknown. Here we demonstrated that the gene associated with retinoid interferon-induced mortality 19 (GRIM-19) was severely depressed or lost in GC and chronic atrophic gastritis (CAG) tissues and its loss contributed to GC tumorigenesis partly by activating STAT3 signaling. In primary human GC tissues, GRIM-19 was frequently depressed or lost and this loss correlated with advanced clinical stage, lymph node metastasis, H. pylori infection and poor overall survival of GC patients. In CAG tissues, GRIM-19 was progressively decreased along with its malignant transformation. Functionally, we indentified an oncogenic role of GRIM-19 loss in promoting GC tumorigenesis. Ectopic GRIM-19 expression suppressed GC tumor formation in vitro and in vivo by inducing cell cycle arrest and apoptosis. Moreover, we revealed that GRIM-19 inhibited STAT3 transcriptional activation and its downstream targets by reducing STAT3 nuclear distribution. Conversely, knockdown of GRIM-19 induced aberrant STAT3 activation and accelerated GC cell growth in vitro and in vivo, and this could be partly attenuated by the blockage of STAT3 activation. In addition, we observed subcellular redistributions of GRIM-19 characterized by peri-nuclear aggregates, non-mitochondria cytoplasmic distribution and nuclear invasion, which should be responsible for reduced STAT3 nuclear distribution. Our studies suggest that mitochondrial GRIM-19 could not only serve as an valuable prognostic biomarker for GC development, but also as a potential therapeutic target for STAT3-dependent carcinogenesis of GC. PMID:27167343

  4. [What is the most important factor for gastric carcinogenesis in Koreans: Helicobacter pylori, host factor or environmental factor?].

    PubMed

    Kim, Hak Yang

    2007-02-01

    Epidemiological data including our studies demonstrated the association between Helicobacter pylori (H. pylori) infection and gastric cancer. However, this significant clinical outcome happens only in a small portion of infected person. This suggests that other contributors including host genetic and environmental factors might be involved in the disease process. Studies on the association between virulent strains of H. pylori and clinical outcomes failed to show significant results in Korea. Cytokine gene polymorphism such as interleukin-1 (IL-1) has been thought to play a role in gastric carcinogenesis. Our studies showed the controversial role of IL-1, TNF-A, IL-10 and IL-2 gene polymorphisms in the development of gastric cancer in Korea. Chronic infection and inflammation leading to tumorigenesis are mediated in part through the recognition of various stimuli by toll-like receptors (TLRs). Our studies on the polymorphisms of TLR4 and TLR2 showed no mutant form in Koreans. These discrepancies might reflect the genetic differences between Caucasians and Koreans or might be due to prevalent genetic polymorphisms with masked effect in gastric carcinogenesis in Koreans. As other candidate risk factors, there are constant or inconsistent results on the effect of dietary intake in gastric cancer. There are numerous similar risk for gastric carcinogenesis with different risk ratio including environmental factors in Caucasians and Koreans. Under the background of prevalent H. pylori infection and genetic polymorphisms, environmental factors including diet may potentiate their role in gastric carcinogenesis in Koreans.

  5. De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis

    PubMed Central

    El-Zaatari, M; Tobias, A; Grabowska, A M; Kumari, R; Scotting, P J; Kaye, P; Atherton, J; Clarke, P A; Powe, D G; Watson, S A

    2007-01-01

    This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/− Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P<0.01) compared to normal mucosa. Sonic hedgehog was reactivated in gastric metaplasia of H. felis-infected mice (3.5-fold increase, P<0.01) compared to pre-metaplastic lesions. Additionally, the Shh target gene, glioma-associated oncogene (Gli)-1, was significantly reduced in the gastric glands of InsGas mice (75% reduction, P<0.05) and reactivated with H. felis infection (P<0.05, base of glands, P<0.01 stroma of metaplastic glands). The ability of H. felis to activate the Shh pathway was investigated by measuring the effect of target cytokine, interleukin-8 (IL-8), on Shh expression in AGS and MGLVA1 cells, which was shown to induce Shh expression at physiological concentrations. H. felis induced the expression of NF-κB in inflammatory infiltrates in vivo, and the expression of the IL-8 mouse homologue, protein KC, in inflammatory infiltrates and metaplastic lesions. Sonic hedgehog pathway reactivation was paralleled with an increase in proliferation of metaplastic lesions (15.75 vs 4.39% in infected vs non-infected mice, respectively, P<0.001). Furthermore, Shh overexpression increased the growth rate of the gastric cancer cell line, AGS. The antiapoptotic protein, bcl-2, was expressed in the stroma of infected mice, along with a second Shh target gene, patched-1 (P=0.0001, stroma of metaplastic gland). This study provides evidence suggesting reactivation of Shh signalling from pre-metaplastic to advanced metaplastic lesions of the stomach and outlines the importance of the Shh pathway as a potential chemoprophylactic target for gastric carcinogenesis. PMID:17505514

  6. Gastric carcinogenesis by duodenal reflux through gut regenerative cell lineage.

    PubMed

    Mukaisho, Ken-Ichi; Miwa, Koichi; Kumagai, Hitomi; Bamba, Masamichi; Sugihara, Hiroyuki; Hattori, Takanori

    2003-11-01

    To elucidate the histogenesis of gastric stump cancer, we performed an operation in rats to make all duodenal contents flow back into the glandular stomach. The subjects were 41 rats, and sequential morphological changes of the duodenogastric stoma and the incidence of stump cancers were studied. Serial sections around the stoma were studied with mucin stains such as paradoxical concanavalin A (Con A), galactose oxidase Schiff (GOS), and high-iron diamine-Alcian blue (HID-AB). An immunohistochemical study on cell proliferation with bromodeoxyuridine (BrdU) was also done. At week 30, pyloric gland type cells positive for Con A first appeared at the base of the intestinal crypts and the fundic glands adjacent to the anastomosis. These glands became large with time, resulting in formation of cystically dilated glands. These gland cells were partially stained with GOS, and then they retained a proliferative activity. These changes seemed to resemble "gastritis cystica profunda" in human remnant stomachs. At 50 and 80 weeks, adenocarcinomas were observed in 4 of 10 rats (40.0%) and in 16 of 21 rats (76.2%), respectively. We have noted that the early change of cystic proliferation of mucous glands resembled the so-called "ulcer associated cell lineage (UACL)" described by others, but our characteristic finding was not only pyloric but also foveolar metaplasia. This pyloric-foveolar metaplasia subsequently led to development of glands with intestinal-type goblet cells, which looked like incomplete intestinal metaplasia. This sequence was different from UACL, and very recently, we proposed a concept of "gut regenerative cell lineage (GRCL); from pyloric-foveolar to with goblet cell metaplasia in regeneration," common to all parts of the gut, and the stump cancer appeared to arise from GRCL.

  7. Chronic inflammation-related DNA damage response: a driving force of gastric cardia carcinogenesis.

    PubMed

    Lin, Runhua; Xiao, Dejun; Guo, Yi; Tian, Dongping; Yun, Hailong; Chen, Donglin; Su, Min

    2015-02-20

    Gastric cardia cancer (GCC) is a highly aggressive disease associated with chronic inflammation. To investigate the relationship between DNA damage response (DDR) and chronic inflammation, we collected 100 non-tumor gastric cardia specimens of Chaoshan littoral, a high-risk region for esophageal and gastric cardia cancer. A significantly higher proportion of severe chronic inflammation was found in dysplastic epithelia (80.9%) in comparison with that in non-dysplastic tissues (40.7%) (P<0.001). Immunohistochemical analysis demonstrated that DNA damage response was parallel with the chronic inflammation degrees from normal to severe inflammation (P<0.05). We found that DNA damage response was progressively increased with the progression of precancerous lesions (P<0.05). These findings provide pathological evidence that persistent chronic inflammation-related DNA damage response may be a driving force of gastric cardia carcinogenesis. Based on these findings, DNA damage response in non-malignant tissues may become a promising biomedical marker for predicting malignant transformation in the gastric cardia.

  8. Gastric cancer stem cells in gastric carcinogenesis, progression, prevention and treatment

    PubMed Central

    Li, Kang; Dan, Zeng; Nie, Yu-Qiang

    2014-01-01

    In recent decades, the study of the mechanism of tumorigenesis has brought much progress to cancer treatment. However, cancer stem cell (CSC) theory has changed previous views of tumors, and has provided a new method for treatment of cancer. The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development, resulting in a new effective strategy for cancer treatment. Gastric CSCs (GCSCs) are the basis for the onset of gastric cancer. They may be derived from gastric stem cells in gastric tissues, or bone marrow mesenchymal stem cells. As with other stem cells, GCSCs highly express drug-resistance genes such as aldehyde dehydrogenase and multidrug resistance, which are resistant to chemotherapy and thus form the basis of drug resistance. Many specific molecular markers such as CD44 and CD133 have been used for identification and isolation of GCSCs, diagnosis and grading of gastric cancer, and research on GCSC-targeted therapy for gastric cancer. Therefore, discussion of the recent development and advancements in GCSCs will be helpful for providing novel insight into gastric cancer treatment. PMID:24833872

  9. Iron deficiency accelerates Helicobacter pylori–induced carcinogenesis in rodents and humans

    PubMed Central

    Noto, Jennifer M.; Gaddy, Jennifer A.; Lee, Josephine Y.; Piazuelo, M. Blanca; Friedman, David B.; Colvin, Daniel C.; Romero-Gallo, Judith; Suarez, Giovanni; Loh, John; Slaughter, James C.; Tan, Shumin; Morgan, Douglas R.; Wilson, Keith T.; Bravo, Luis E.; Correa, Pelayo; Cover, Timothy L.; Amieva, Manuel R.; Peek, Richard M.

    2012-01-01

    Gastric adenocarcinoma is strongly associated with Helicobacter pylori infection; however, most infected persons never develop this malignancy. H. pylori strains harboring the cag pathogenicity island (cag+), which encodes CagA and a type IV secretion system (T4SS), induce more severe disease outcomes. H. pylori infection is also associated with iron deficiency, which similarly augments gastric cancer risk. To define the influence of iron deficiency on microbial virulence in gastric carcinogenesis, Mongolian gerbils were maintained on iron-depleted diets and infected with an oncogenic H. pylori cag+ strain. Iron depletion accelerated the development of H. pylori–induced premalignant and malignant lesions in a cagA-dependent manner. H. pylori strains harvested from iron-depleted gerbils or grown under iron-limiting conditions exhibited enhanced virulence and induction of inflammatory factors. Further, in a human population at high risk for gastric cancer, H. pylori strains isolated from patients with the lowest ferritin levels induced more robust proinflammatory responses compared with strains isolated from patients with the highest ferritin levels, irrespective of histologic status. These data demonstrate that iron deficiency enhances H. pylori virulence and represents a measurable biomarker to identify populations of infected persons at high risk for gastric cancer. PMID:23257361

  10. Identification of novel genes involved in gastric carcinogenesis by suppression subtractive hybridization.

    PubMed

    Mottaghi-Dastjerdi, N; Soltany-Rezaee-Rad, M; Sepehrizadeh, Z; Roshandel, G; Ebrahimifard, F; Setayesh, N

    2015-01-01

    Gastric cancer (GC) is one of the most common and life-threatening types of malignancies. Identification of the differentially expressed genes in GC is one of the best approaches for establishing new diagnostic and therapeutic targets. Furthermore, these investigations could advance our knowledge about molecular biology and the carcinogenesis of this cancer. To screen for the overexpressed genes in gastric adenocarcinoma, we performed suppression subtractive hybridization (SSH) on gastric adenocarcinoma tissue and the corresponding normal gastric tissue, and eight genes were found to be overexpressed in the tumor compared with those of the normal tissue. The genes were ribosomal protein L18A, RNase H2 subunit B, SEC13, eukaryotic translation initiation factor 4A1, tetraspanin 8, cytochrome c oxidase subunit 2, NADH dehydrogenase subunit 4, and mitochondrially encoded ATP synthase 6. The common functions among the identified genes include involvement in protein synthesis, involvement in genomic stability maintenance, metastasis, metabolic improvement, cell signaling pathways, and chemoresistance. Our results provide new insights into the molecular biology of GC and drug discovery: each of the identified genes could be further investigated as targets for prognosis evaluation, diagnosis, treatment, evaluation of the response to new anticancer drugs, and determination of the molecular pathogenesis of GC.

  11. [Carcinogenesis].

    PubMed

    Martín de Civetta, María Teresa; Civetta, Julio Domingo

    2011-01-01

    Cell division is controlled by stimulatory and inhibitory systems.The origin of cancer is monoclonal, and in order that a normal cell switches its phenotype and becomes a neoplastic cell, genetic mutations must occur on it.These genetic mutations modify the products that in normal conditions the gene would codify and, finally, cause cancer. Cancer may be hereditary (due to mutations in one or both of germinal cells alleles) or sporadic (due to action of environmental mutagenic agents).The mechanisms that may cause alterations on genes may be genetic or epigenetic. Genetic mechanisms occur when structural alterations of genome are present and the epigenetic processes occur due to enzymatic alterations or alterations on its substrates. Carcinogenesis has three stages: initiation, promotion and progression.The last of these stages, progression, is exclusive of malignant transformation and implies the capacity to invade surrounding or distant tissues. For metastasis to take place, many mechanisms are required: angiogenesis, matrix degradation, cell migration, evasion of host immune response and metastatic colonization. This article presents a partial review of current bibliography about concepts related to carcinogenesis and conveys the minimum necessary information to achieve an understanding of this complex process.

  12. Epigenetic modulation associated with carcinogenesis and prognosis of human gastric cancer.

    PubMed

    Sonohara, Fuminori; Inokawa, Yoshikuni; Hayashi, Masamichi; Kodera, Yasuhiro; Nomoto, Shuji

    2017-05-01

    Gastric cancer (GC) is a leading cause of cancer-related death, particularly in Asia. Epidemiological and other clinical studies have identified an association between a number of risk factors, including Helicobacter pylori, and GC. A number of studies have also examined genetic changes associated with the development and progression of GC. When considering the clinical significance of the expression of a specific gene, its epigenetic modulation should be considered. Epigenetic modulation appears to be a primary driver of changes in gastric tissue that promotes carcinogenesis and progression of GC and other neoplasms. The role of epigenetic modulation in GC carcinogenesis and progression has been widely studied in recent years. In the present review, recent results of epigenetic modulation associated with GC and their effects on clinical outcome are examined, with particular respect to DNA methylation, histone modulation and non-coding RNA. A number of studies indicate that epigenetic changes in the expression of specific genes critically affect their clinical significance and further study may reveal epigenetic changes as the basis for targeted molecular therapy or novel biomarkers that predict GC prognosis or extension of this often fatal disease.

  13. Role of EZH2 protein expression in gastric carcinogenesis among Asians: a meta-analysis.

    PubMed

    Guo, Lin; Yang, Teng-Fei; Liang, Shi-Chao; Guo, Ji-Xiang; Wang, Qiang

    2014-07-01

    The present meta-analysis aggregated the results of relevant studies to identify the role of zeste homolog 2 (EZH2) expression in gastric carcinogenesis among Asians. Related articles were found by searching the following electronic databases without language restrictions: PubMed, SpringerLink, Karger Medical and Scientific Publishers, Chinese Biomedical Database (CBM), Chinese National Knowledge Infrastructure (CNKI), and Google Scholar. Meta-analysis was performed using STATA statistical software. Crude odds ratios (ORs) or hazard ratios (HRs) with their corresponding 95 % confidence interval (95 % CI) were calculated. Ten relevant studies, which enrolled a total of 872 gastric cancer patients, were selected for statistical analysis. The most important findings of our meta-analysis was that cancer tissues exhibited higher expression levels of EZH2 protein than normal, adjacent and benign tissues (cancer tissues vs normal tissues: OR = 32.15, 95 % CI 22.58 ~ 45.79, P < 0.001; cancer tissues vs adjacent tissues: OR = 16.10, 95 % CI 11.35 ~ 22.84, P < 0.001; cancer tissues vs benign tissues: OR = 2.66, 95 % CI 1.89 ~ 3.75, P < 0.001; respectively). Furthermore, we observed positive correlations between EZH2 expression and the TNM stage (OR = 2.86, 95 % CI 1.72 ~ 4.75, P < 0.001) as well as lymph node metastasis (OR = 3.02, 95 % CI 2.01 ~ 4.53, P < 0.001) of patients with gastric carcinoma. The correlation between EZH2 expression and gastric cancer prognosis was also evaluated in the meta-analysis. Statistical analysis demonstrated that the overall survival (OS) of EZH2-negative patients was shorter than that of patients with positive expressions of EZH2 (HR = 0.54, 95 % CI = 0.05 ~ 1.03, P = 0.032). Our meta-analysis confirmed the view that EZH2 expression might participate in the development of gastric carcinogenesis. Thus, EZH2 protein may be a valuable biomarker for the diagnosis and prognosis of gastric cancer.

  14. High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing.

    PubMed

    Sepulveda, Jorge L; Gutierrez-Pajares, Jorge L; Luna, Aesis; Yao, Yuan; Tobias, John W; Thomas, Steven; Woo, Yanghee; Giorgi, Federico; Komissarova, Elena V; Califano, Andrea; Wang, Timothy C; Sepulveda, Antonia R

    2016-02-01

    Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer.

  15. Hydrogen Metabolism in Helicobacter pylori Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation

    PubMed Central

    Wang, Ge; Romero-Gallo, Judith; Benoit, Stéphane L.; Piazuelo, M. Blanca; Dominguez, Ricardo L.; Morgan, Douglas R.; Peek, Richard M.

    2016-01-01

    ABSTRACT A known virulence factor of Helicobacter pylori that augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δhyd mutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO) was used to specifically inhibit the H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhyd strain showed a decreased frequency of DNA transformation, suggesting that H. pylori hydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δhyd strain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δhyd strain. By examining the hydrogenase activities from well-defined clinical H. pylori isolates, we observed that strains isolated from cancer patients (n = 6) have a significantly higher hydrogenase (H2/O2) activity than the strains isolated from gastritis patients (n = 6), further supporting an association between H. pylori hydrogenase activity and gastric carcinogenesis in humans. PMID:27531909

  16. STUDIES INTO THE MECHANISMS OF POTASSIUM BROMATE INDUCED THYROID CARCINOGENESIS

    EPA Science Inventory

    Studies into the Mechanisms of Potassium Bromate Induced Thyroid Carcinogenesis.

    Potassium bromate (KBrO3) occurs in finished drinking water as a by-product of the ozonation disinfection process and has been found to induce thyroid follicular cell tumors in the rat after ...

  17. Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis.

    PubMed

    Min, Byung-Hoon; Hwang, Jinha; Kim, Nayoung Kd; Park, Gibeom; Kang, So Young; Ahn, Sangjeong; Ahn, Soomin; Ha, Sang Yun; Lee, Yun Kyung; Kushima, Ryoji; Van Vrancken, Michael; Kim, Min Jung; Park, Changho; Park, Ha Young; Chae, Jeesoo; Jang, Se Song; Kim, Sung Jin; Kim, Young-Ho; Kim, Jong-Il; Kim, Kyoung-Mee

    2016-11-01

    Several recurrent mutations and epigenetic changes have been identified in advanced gastric cancer, but the genetic alterations associated with early gastric carcinogenesis and malignant transformation remain unclear. We investigated the genomic and transcriptomic landscape of adenomas with low-grade dysplasia (LGD) and high-grade dysplasia (HGD), and intestinal-type early gastric cancer (EGC). The results were validated in an independent cohort that included EGCs directly adjacent to adenoma (EGC-adenomas) that were in the process of malignant transformation, and de novo EGCs that do not seem to have been derived from adenoma. The expression patterns clearly divided into normal, LGD, and EGC, whereas those of HGD overlapped with LGD or EGC. These results suggest that HGD is the critical stage determining malignant transformation. We found that genes related to focal adhesion and extracellular matrix receptor interaction pathways were upregulated as LGD progressed to EGC, whereas canonical Wnt signalling and peroxisome proliferator-activated receptor (PPAR) signalling pathway genes were downregulated in EGC. Genomic alterations such as somatic mutation, gene fusion and copy number variation increased gradually from LGD to EGC. APC mutations were present in 67% of LGDs, 58% of HGDs, and 18% of EGCs. RNF43 mutations were present only in HGD and EGC, and TP53 mutations were present only in EGC. In a validation cohort, RNF43 mutations were present in 35.2% of EGC-adenomas, but in only 8.6% of de novo EGCs. This is the first study to investigate the genomic and transcriptomic landscape of multistep gastric carcinogenesis. We investigated important alterations and their related pathways in each step as tumours progressed from LGD to HGD and eventually to EGC. We suggest that mutations and downregulation of RNF43 may play a critical role in the transition from adenoma to carcinoma. Given these findings and Wnt dependency in tumours with RNF43 mutation, intestinal

  18. Gastrin Is an Essential Cofactor for Helicobacter-Associated Gastric Corpus Carcinogenesis in C57BL/6 Mice

    PubMed Central

    Takaishi, Shigeo; Tu, Shuiping; Dubeykovskaya, Zinaida A.; Whary, Mark T.; Muthupalani, Sureshkumar; Rickman, Barry H.; Rogers, Arlin B.; Lertkowit, Nantaporn; Varro, Andrea; Fox, James G.; Wang, Timothy C.

    2009-01-01

    We have previously described a synergistic interaction between hypergastrinemia and Helicobacter felis infection on gastric corpus carcinogenesis in FVB/N mice housed under specific-pathogen-free conditions. However, gastrin-deficient (GAS-KO) mice on a mixed C57BL/6/129Sv genetic background maintained in conventional housing were reported to develop spontaneous gastric antral tumors. Therefore, we investigated the role of gastrin in Helicobacter-associated gastric carcinogenesis in H. felis-infected mice on a uniform C57BL/6 background housed in specific-pathogen-free conditions. Hypergastrinemic transgenic (INS-GAS) mice, GAS-KO mice, and C57BL/6 wild-type mice were infected with H. felis for either 12 or 18 months. At 12 months postinfection, INS-GAS mice had mild corpus dysplasia, while B6 wild-type mice had either severe gastritis or metaplasia, and GAS-KO mice had only mild to moderate gastritis. At 18 months postinfection, both INS-GAS and B6 wild-type mice had both severe atrophic gastritis and corpus dysplasia, while GAS-KO mice had severe gastritis with mild gastric atrophy, but no corpus dysplasia. In contrast, both GAS-KO and B6 wild-type mice had mild to moderate antral dysplasia, while INS-GAS mice did not. H. felis antral colonization remained stable over time among the three groups of mice. These results point to a distinct effect of gastrin on carcinogenesis of both the gastric corpus and antrum, suggesting that gastrin is an essential cofactor for gastric corpus carcinogenesis in C57BL/6 mice. PMID:19556515

  19. Hydrogen Metabolism in Helicobacter pylori Plays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation.

    PubMed

    Wang, Ge; Romero-Gallo, Judith; Benoit, Stéphane L; Piazuelo, M Blanca; Dominguez, Ricardo L; Morgan, Douglas R; Peek, Richard M; Maier, Robert J

    2016-08-16

    A known virulence factor of Helicobacter pylori that augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δhyd mutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO) was used to specifically inhibit the H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhyd strain showed a decreased frequency of DNA transformation, suggesting that H. pylori hydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δhyd strain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δhyd strain. By examining the hydrogenase activities from well-defined clinical H. pylori isolates, we observed that strains isolated from cancer patients (n = 6) have a significantly higher hydrogenase (H2/O2) activity than the strains isolated from gastritis patients (n = 6), further supporting an association between H. pylori hydrogenase activity and gastric carcinogenesis in humans. Hydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen's (H. pylori) use of molecular hydrogen, a

  20. Yin Yang 1 is a target of microRNA-34 family and contributes to gastric carcinogenesis.

    PubMed

    Wang, An-Ming; Huang, Tzu-Ting; Hsu, Kai-Wen; Huang, Kuo-Hung; Fang, Wen-Liang; Yang, Muh-Hwa; Lo, Su-Shun; Chi, Chin-Wen; Lin, Jing-Jer; Yeh, Tien-Shun

    2014-07-15

    Gastric cancer is the second leading cause of cancer-related death worldwide. Herein, we investigated the role of transcription factor Yin Yang 1 (YY1), a multi-functional protein, in tumorigenesis of gastric cancer cells. Results showed that YY1 contributed to gastric carcinogenesis of SC-M1 cells including growth, viability, and abilities of colony formation, migration, invasion, and tumorsphere formation. Levels of pluripotency genes CD44, Oct4, SOX-2, and Nanog were also up-regulated by YY1 in SC-M1 cells. Additionally, the 3'-untranslated region (3'-UTR) of YY1 mRNA was the target of microRNA-34 (miR-34) family consisting of miR-34a, miR-34b, and miR-34c. Overexpression of miR-34 family suppressed carcinogenesis through down-regulation of YY1 in NUGC-3 gastric cancer cells scarcely expressing miR-34 family. Alternatively, knockdown of miR-34 family promoted tumorigenesis via up-regulation of YY1 in SC-M1 and AZ521 gastric cancer cells with higher levels of miR-34 family. The miR-34 family also affected tumorsphere ultra-structure and inhibited the xenografted tumor growth as well as lung metastasis of SC-M1 cells through YY1. Expressions of miR-34a and miR-34c in gastric cancer tissues of patients were lower than those in normal tissues. Taken together, these results suggest that miR-34 family-YY1 axis plays an important role in the control of gastric carcinogenesis.

  1. PBX1 attributes as a determinant of connexin 32 downregulation in Helicobacter pylori-related gastric carcinogenesis.

    PubMed

    Liu, Xiao-Ming; Xu, Can-Xia; Zhang, Lin-Fang; Huang, Li-Hua; Hu, Ting-Zi; Li, Rong; Xia, Xiu-Juan; Xu, Lin-Yong; Luo, Ling; Jiang, Xiao-Xia; Li, Ming

    2017-08-07

    To clarify the mechanisms of connexin 32 (Cx32) downregulation by potential transcriptional factors (TFs) in Helicobacter pylori (H. pylori)-associated gastric carcinogenesis. Approximately 25 specimens at each developmental stage of gastric carcinogenesis [non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia and gastric carcinoma (GC)] with H. pylori infection [H. pylori (+)] and 25 normal gastric mucosa (NGM) without H. pylori infection [H. pylori (-)] were collected. After transcriptional factor array analysis, the Cx32 and PBX1 expression levels of H. pylori-infected tissues from the developmental stages of GC and NGM with no H. pylori infection were measured by real-time polymerase chain reaction (RT-PCR) and Western blot analysis. Regarding H. pylori-infected animal models, the Cx32 and PBX1 mRNA expression levels and correlation between the gastric mucosa from 10 Mongolian gerbils with long-term H. pylori colonization and 10 controls were analyzed. PBX1 and Cx32 mRNA and protein levels were further studied under the H. pylori-infected condition as well as PBX1 overexpression and knockdown conditions in vitro. Incremental PBX1 was first detected by TF microarray in H. pylori-related gastric carcinogenesis. The identical trend of PBX1 and Cx32 expression was confirmed in the developmental stages of H. pylori-related clinical specimens. The negative correlation of PBX1 and Cx32 was confirmed in H. pylori-infected Mongolian gerbils. Furthermore, decreased PBX1 expression was detected in the normal gastric epithelial cell line GES-1 with H. pylori infection. Enforced overexpression or RNAi-mediated knockdown of PBX1 contributed to the diminished or restored Cx32 expression in GES-1 and the gastric carcinoma cell line BGC823, respectively. Finally, dual-luciferase reporter assay in HEK293T cells showed that Cx32 promoter activity decreased by 30% after PBX1 vector co-transfection, indicating PBX1 as a transcriptional downregulator

  2. Chemopreventive Activity of MGN-3/Biobran Against Chemical Induction of Glandular Stomach Carcinogenesis in Rats and Its Apoptotic Effect in Gastric Cancer Cells.

    PubMed

    Badr El-Din, Nariman K; Abdel Fattah, Salma M; Pan, Deyu; Tolentino, Lucilene; Ghoneum, Mamdooh

    2016-12-01

    In the current study, we investigated the chemopreventive activity of arabinoxylan rice bran, MGN-3/Biobran, against chemical induction of glandular stomach carcinogenesis in rats. Gastric cancer was induced by carcinogen methylnitronitrosoguanidine (MNNG), and rats received MNNG alone or MNNG plus Biobran (40 mg/kg body weight) for a total of 8 months. Averaged results from 2 separate readings showed that exposure to MNNG plus Biobran caused gastric dysplasia and cancer (adenocarcinoma) in 4.5/12 rats (9/24 readings, 37.5%), with 3.5/12 rats (7/24 readings, 29.2%) showing dysplasia and 1/12 rats (8.3%) developing adenocarcinoma. In contrast, in rats treated with MNNG alone, 8/10 (80%) developed dysplasia and adenocarcinoma, with 6/10 rats (60%) showing dysplasia and 2/10 rats (20%) developing adenocarcinoma. The effect of combining both agents was also associated with significant suppression of the expression of the tumor marker Ki-67 and remarkable induction in the apoptotic gastric cancer cells via mitochondrial-dependent pathway as indicated by the upregulation in p53 expression, Bax expression, downregulation in Bcl-2 expression, an increase in Bax/Bcl-2 ratio, and an activation of caspase-3. In addition, Biobran treatment induced cell-cycle arrest in the subG1 phase, where the hypodiploid cell population was markedly increased. Moreover, Biobran treatment protected rats against MNNG-induced significant decrease in lymphocyte levels. We conclude that Biobran provides protection against chemical induction of glandular stomach carcinogenesis in rats and may be useful for the treatment of human patients with gastric cancer.

  3. A nonsense mutation in the Xeroderma pigmentosum complementation group F (XPF) gene is associated with gastric carcinogenesis.

    PubMed

    Wei, Zhong-Hua; Guo, Wen-Huan; Wu, Jun; Suo, Wen-Hao; Fu, Guo-Hui

    2014-03-10

    XPF/ERCC1 endonuclease is required for DNA lesion repair. To assess effects of a C2169A nonsense mutation in XPF at position 2169 in gastric cancer tissues and cell lines, genomic DNA was extracted from blood samples of 488 cancer patients and 64 gastric tumors. The mutation was mapped using a TaqMan MGB probe. In addition, gastric cancer cell lines were transfected with mutated XPF to explore XPF/ERCC1 interaction, XPF degradation, and DNA repair by a comet assay. The C2169A mutation was not detected in 488 samples of blood genomic DNA, yet was found in 32 of 64 gastric cancer tissue samples (50.0%), resulting in a 194C-terminal amino acid loss in XPF protein and lower expression. Laser micro-dissection confirmed that this point mutation was not present in surrounding normal tissues from the same patients. The truncated form of XPF (tXPF) impaired interaction with ERCC1, was rapidly degraded via ubiquitination, and resulted in reduced DNA repair. In gastric cancers, the mutation was monoallelic, indicating that XPF is a haplo-insufficient DNA repair gene. As the C2169A mutation is closely associated with gastric carcinogenesis in the Chinese population, our findings shine light on it as a therapeutic target for early diagnosis and treatment of gastric cancer.

  4. Differential regulation analysis reveals dysfunctional regulatory mechanism involving transcription factors and microRNAs in gastric carcinogenesis.

    PubMed

    Li, Quanxue; Li, Junyi; Dai, Wentao; Li, Yi-Xue; Li, Yuan-Yuan

    2017-03-01

    Gastric cancer (GC) is one of the most incident malignancies in the world. Although lots of featured genes and microRNAs (miRNAs) have been identified to be associated with gastric carcinogenesis, underlying regulatory mechanisms still remain unclear. In order to explore the dysfunctional mechanisms of GC, we developed a novel approach to identify carcinogenesis relevant regulatory relationships, which is characterized by quantifying the difference of regulatory relationships between stages. Firstly, we applied the strategy of differential coexpression analysis (DCEA) to transcriptomic datasets including paired mRNA and miRNA of gastric samples to identify a set of genes/miRNAs related to gastric cancer progression. Based on these genes/miRNAs, we constructed conditional combinatorial gene regulatory networks (cGRNs) involving both transcription factors (TFs) and miRNAs. Enrichment of known cancer genes/miRNAs and predicted prognostic genes/miRNAs was observed in each cGRN. Then we designed a quantitative method to measure differential regulation level of every regulatory relationship between normal and cancer, and the known cancer genes/miRNAs proved to be ranked significantly higher. Meanwhile, we defined differentially regulated link (DRL) by combining differential regulation, differential expression and the regulation contribution of the regulator to the target. By integrating survival analysis and DRL identification, three master regulators TCF7L1, TCF4, and MEIS1 were identified and testable hypotheses of dysfunctional mechanisms underlying gastric carcinogenesis related to them were generated. The fine-tuning effects of miRNAs were also observed. We propose that this differential regulation network analysis framework is feasible to gain insights into dysregulated mechanisms underlying tumorigenesis and other phenotypic changes. Copyright © 2017. Published by Elsevier B.V.

  5. Luteolin supplementation adjacent to aspirin treatment reduced dimethylhydrazine-induced experimental colon carcinogenesis in rats.

    PubMed

    Osman, Neamt H A; Said, Usama Z; El-Waseef, Ahmed M; Ahmed, Esraa S A

    2015-02-01

    Previous studies have shown that aspirin is used in colon cancer treatment. However, long-term of Aspirin usage is limited to gastric and renal toxicity. Luteolin (LUT) has cancer prevention and anti-inflammatory effects. The present study was designed to investigate the effect of LUT supplementation and Aspirin treatment in dimethylhydrazine (DMH)-induced carcinogenesis in rats. DMH (20 mg/kg BW/week) treated rats received gavages with Aspirin (50 mg/kg BW/week) and LUT (0.2 mg/kg BW/day) for 15 weeks. DMH injections induce colon polyps and renal bleeding, significantly increasing carcinoembryonic antigen (CEA), cyclooxygenase-2 (COX-2), oxidative stress, and kidney function tests and reducing antioxidant markers. Either Aspirin or LUT gavages alone or combined produce a significant decrease in colon polyp number and size, significantly decreasing CEA, COX-2, and oxidative stress and increasing antioxidant markers. In conclusion, the supplementations of LUT adjacent to Aspirin in the treatment of DMH-induced carcinogenesis in rats reflect a better effect than the use of Aspirin alone.

  6. Mechanisms of acrylamide induced rodent carcinogenesis.

    PubMed

    Klaunig, James E; Kamendulis, Lisa M

    2005-01-01

    observed carcinogenicity of acrylamide. SHE cell studies showed that glutathione (GSH) modulation by acrylamide was important in the cell transformation process. Treatment with a sulfhydryl donor compound (NAC) reduced acrylamide transformation while depletion of GSH (BSO) resulted in an enhancement of transformation. In summary, acrylamide caused both an increase in DNA synthesis and DNA damage in mammalian tissues and cells suggesting that DNA reactivity and cell proliferation, in concert, may contribute to the observed acrylamide-induced carcinogenicity in the rat and has implication on the possible risk for human neoplasm development.

  7. Colon epithelial proliferation and carcinogenesis in diet-induced obesity.

    PubMed

    Takahashi, Hirokazu; Hosono, Kunihiro; Endo, Hiroki; Nakajima, Atsushi

    2013-12-01

    Colorectal cancer is the third leading cause of cancer death in Japan and the United States and is strongly associated with obesity, especially visceral obesity. Several metabolic mediators, such as adiponectin, have been suspected to play a role in obesity-related carcinogenesis. In a previous human study, the existence of a significant correlation between the number of human dysplastic aberrant crypt foci (ACF) and the visceral fat area was demonstrated, and also that of a significant inverse correlation between the number of dysplastic ACF and the plasma adiponectin level. Other studies have investigated the effect of adiponectin under the normal and high-fat diet conditions in a mouse model of azoxymethane-induced colon cancer. Enhanced formation of both ACF and tumors was observed in the adiponectin-deficient mice, as compared with that in the wild-type, under the high-fat diet condition but not under the normal diet condition. Furthermore, that the 5'-AMP-activated kinase/mammalian target of rapamycin pathway is involved in the promotion of colorectal carcinogenesis in adiponectin-deficient mice under the high-fat diet condition was shown. Therefore, that the 5'-AMP-activated kinase/mammalian target of rapamycin signaling pathway may play an important role in colorectal carcinogenesis was speculated. Metformin, a biguanide derivative widely used in the treatment of diabetes mellitus, has been shown to exert a suppressive effect on ACF formation in both mouse models and humans. Therefore, metformin might be a promising candidate as a safe drug for chemoprevention of colorectal carcinogenesis. Further studies with high evidence levels, such as randomized, controlled studies, are needed to clarify these relationships. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  8. Langerhans Cells Facilitate UVB-induced Epidermal Carcinogenesis

    PubMed Central

    Lewis, Julia M.; Bürgler, Christina D.; Freudzon, Marianna; Golubets, Kseniya; Gibson, Juliet F.; Filler, Renata B.; Girardi, Michael

    2015-01-01

    Ultraviolet B (UVB) light is considered the major environmental inducer of human keratinocyte DNA mutations, including within the tumor-suppressor gene p53, and chronic exposure is associated with cutaneous squamous cell carcinoma (SCC) formation. Langerhans cells (LC) comprise a dendritic network within the suprabasilar epidermis, yet the role of LC in UVB-induced carcinogenesis is largely unknown. Herein, we show that LC-intact epidermis develops UVB-induced tumors more readily than LC-deficient epidermis. While levels of epidermal cyclopyrimidine dimers (CPD) following acute UVB exposure are equivalent in the presence or absence of LC, chronic UVB-induced p53 mutant clonal islands expand more readily in association with LC which remain largely intact and are preferentially found in proximity to the expanding mutant keratinocyte populations. The observed LC facilitation of mutant p53 clonal expansion is completely αβ and γδ T-cell independent, and is associated with increased intraepidermal expression of interleukin (IL)-22 and the presence of group 3 innate lymphoid cells (ILC3). These data demonstrate that LC play a key role in UVB-induced cutaneous carcinogenesis, and suggest that LC locally stimulate keratinocyte proliferation and innate immune cells that provoke tumor outgrowth. PMID:26053049

  9. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

    PubMed Central

    Meira, Lisiane B.; Bugni, James M.; Green, Stephanie L.; Lee, Chung-Wei; Pang, Bo; Borenshtein, Diana; Rickman, Barry H.; Rogers, Arlin B.; Moroski-Erkul, Catherine A.; McFaline, Jose L.; Schauer, David B.; Dedon, Peter C.; Fox, James G.; Samson, Leona D.

    2008-01-01

    Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium–induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis. PMID:18521188

  10. bak deletion stimulates gastric epithelial proliferation and enhances Helicobacter felis-induced gastric atrophy and dysplasia in mice.

    PubMed

    Duckworth, C A; Abuderman, A A; Burkitt, M D; Williams, J M; O'Reilly, L A; Pritchard, D M

    2015-09-15

    Helicobacter infection causes a chronic superficial gastritis that in some cases progresses via atrophic gastritis to adenocarcinoma. Proapoptotic bak has been shown to regulate radiation-induced apoptosis in the stomach and colon and also susceptibility to colorectal carcinogenesis in vivo. Therefore we investigated the gastric mucosal pathology following H. felis infection in bak-null mice at 6 or 48 wk postinfection. Primary gastric gland culture from bak-null mice was also used to assess the effects of bak deletion on IFN-γ-, TNF-α-, or IL-1β-induced apoptosis. bak-null gastric corpus glands were longer, had increased epithelial Ki-67 expression, and contained fewer parietal and enteroendocrine cells compared with the wild type (wt). In wt mice, bak was expressed at the luminal surface of gastric corpus glands, and this increased 2 wk post-H. felis infection. Apoptotic cell numbers were decreased in bak-null corpus 6 and 48 wk following infection and in primary gland cultures following cytokine administration. Increased gastric epithelial Ki-67 labeling index was observed in C57BL/6 mice after H. felis infection, whereas no such increase was detected in bak-null mice. More severe gastric atrophy was observed in bak-null compared with C57BL/6 mice 6 and 48 wk postinfection, and 76% of bak-null compared with 25% of C57BL/6 mice showed evidence of gastric dysplasia following long-term infection. Collectively, bak therefore regulates gastric epithelial cell apoptosis, proliferation, differentiation, mucosal thickness, and susceptibility to gastric atrophy and dysplasia following H. felis infection. Copyright © 2015 the American Physiological Society.

  11. Effect of Thyroid Function on MNU-Induced Mammary Carcinogenesis.

    PubMed

    Vermey, Mackenzie L; Marks, Gregory T; Baldridge, Monika G

    2015-06-01

    Mammary cancer is a disease that affects many women. Extensive research has been conducted to elucidate which variables are involved in the development of this cancer. Studies have highlighted thyroid function as a modulator of tumor growth and development. Thyroxine and 3,3',5-triiodothyronine are responsible for regulating the development, differentiation, homeostasis, and metabolism of cells in the body including mammary tissue. Thyroid hormones also have estrogen-like effects on mammary cancer cell growth by regulating the estrogen receptor. The present study was designed to determine whether medically induced hyperthyroidism increases the multiplicity, prevalence, and mammary tumor burden in rats; and to elucidate whether surgically induced hypothyroidism conversely attenuates the rate of mammary cancer cell growth. Female Sprague-Dawley rats were randomly divided into three groups (euthyroid-control, hyperthyroid, and hypothyroid). Hyperthyroidism was induced via oral administration of levothyroxine; whereas, hypothyroidism was induced by thyroidectomy. Mammary carcinogenesis was induced with a single intraperitoneal injection of N-methyl-N-nitrosurea (MNU). Rats were sacrificed at 38 weeks, and the mammary tumors were excised, fixed for histology and analyzed. Analysis included evaluation of malignancy and immunohistochemistry for ER. MNU-induced mammary carcinogenesis among the groups resulted in a significant difference in tumor burden. The hyperthyroid group had a statistically higher tumor burden than did the euthyroid group, and the hypothyroid group had no tumors of mammary tissue origin at 38 weeks. All excised mammary tumors were ER alpha negative. These data support the hypothesis that thyroid function is one of potentially many factors that contribute to modulation of MNU-induced mammary tumor growth.

  12. Viral Carcinogenesis: Factors Inducing DNA Damage and Virus Integration

    PubMed Central

    Chen, Yan; Williams, Vonetta; Filippova, Maria; Filippov, Valery; Duerksen-Hughes, Penelope

    2014-01-01

    Viruses are the causative agents of 10%–15% of human cancers worldwide. The most common outcome for virus-induced reprogramming is genomic instability, including accumulation of mutations, aberrations and DNA damage. Although each virus has its own specific mechanism for promoting carcinogenesis, the majority of DNA oncogenic viruses encode oncogenes that transform infected cells, frequently by targeting p53 and pRB. In addition, integration of viral DNA into the human genome can also play an important role in promoting tumor development for several viruses, including HBV and HPV. Because viral integration requires the breakage of both the viral and the host DNA, the integration rate is believed to be linked to the levels of DNA damage. DNA damage can be caused by both endogenous and exogenous factors, including inflammation induced by either the virus itself or by co-infections with other agents, environmental agents and other factors. Typically, cancer develops years to decades following the initial infection. A better understanding of virus-mediated carcinogenesis, the networking of pathways involved in transformation and the relevant risk factors, particularly in those cases where tumorigenesis proceeds by way of virus integration, will help to suggest prophylactic and therapeutic strategies to reduce the risk of virus-mediated cancer. PMID:25340830

  13. Gastric and oesophageal carcinogenesis: models for the identification of risk and protective factors.

    PubMed

    Newberne, P M; Charnley, G; Adams, K; Cantor, M; Roth, D; Supharkarn, V; Fong, L

    1986-01-01

    Male weanling rats of the Charles River Sprague-Dawley strain were exposed to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the water for 3 months at the concentration of 75 ml/litre. Other real or potential risk factors were administered, alone or in combination with MNNG. When MNNG was administered in combination with NaCl, bile acids, aspirin or BHA, forestomach tumours were enhanced. MNNG-induced tumours were inhibited by selenium or by difluoromethylornithine, an ornithine decarboxylase inhibitor. BHA alone caused forestomach tumours. When BHA was administered by dietary means or by gavage, alone or in combination with MNNG, the gavage method resulted in greater tumorigenesis than dietary exposure. This increase was associated with increased [3H]thymidine labelling of forestomach epithelium and increased hyperplasia. Oesophageal carcinogenesis induced by methylbenzylnitrosamine (MBN) was enhanced by zinc deficiency, alcohol and 13-cis-retinoic acid. Zinc deficiency also resulted in oesophageal tumours in rats exposed to the hepatocarcinogen dimethylnitrosamine. Riboflavin deficiency injured oral and oesophageal epithelium and increased sensitivity to MBN-induced oesophageal tumours.

  14. The roles of BTG3 expression in gastric cancer: a potential marker for carcinogenesis and a target molecule for gene therapy.

    PubMed

    Gou, Wen-feng; Yang, Xue-feng; Shen, Dao-fu; Zhao, Shuang; Liu, Yun-peng; Sun, Hong-zhi; Takano, Yasuo; Su, Rong-jian; Luo, Jun-sheng; Zheng, Hua-chuan

    2015-08-14

    BTG (B-cell translocation gene) can inhibit cell proliferation, metastasis and angiogenesis, cell cycle progression, and induce differentiation in various cells. Here, we found that BTG3 overexpression inhibited proliferation, induced S/G2 arrest, differentiation, autophagy, apoptosis, suppressed migration and invasion in MKN28 and MGC803 cells (p < 0.05). BTG3 transfectants showed a higher mRNA expression of p27, Bax, 14-3-3, Caspase-3, Caspase-9, Beclin 1, NF-κB, IL-1, -2, -4, -10 and -17, but a lower mRNA expression of p21, MMP-9 and VEGF than the control and mock (p < 0.05). At protein level, BTG3 overexpression increased the expression of CDK4, AIF, LC-3B, Beclin 1 and p38 (p < 0.05), but decreased the expression of p21 and β-catenin in both transfectants (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG3 transfectants showed lower viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05). BTG3 expression was restored after 5-aza-2'-deoxycytidine or MG132 treatment in gastric cancer cells. BTG3 expression was decreased in gastric cancer in comparison to the adjacent mucosa (p < 0.05), and positively correlated with venous invasion and dedifferentiation of cancer (p < 0.05). It was suggested that BTG3 expression might contribute to gastric carcinogenesis. BTG3 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer.

  15. Chemopreventive potential of zinc in experimentally induced colon carcinogenesis.

    PubMed

    Dani, Vijayta; Goel, Ajay; Vaiphei, K; Dhawan, D K

    2007-06-15

    The present study was performed to evaluate the efficacy of zinc treatment on colonic antioxidant defense system and histoarchitecture in 1,2-dimethylhydrazine- (DMH) induced colon carcinogenesis in male Sprague-Dawley rats. The rats were segregated into four groups viz., normal control, DMH treated, zinc treated, DMH+zinc treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 16 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227 mg/L in drinking water, ad libitum for the entire duration of the study. Increased tumor incidence, tumor size and number of aberrant crypt foci (ACF) were accompanied by a decrease in lipid peroxidation, glutathione-S-transferase, superoxide dismutase (SOD) and catalase. On the contrary, significantly increased levels of reduced glutathione (GSH) and glutathione reductase (GR) were observed in DMH treated rats. Administration of zinc to DMH treated rats significantly decreased the tumor incidence, tumor size and aberrant crypt foci number with simultaneous enhancement of lipid peroxidation, SOD, catalase and glutathione-S-transferase. Further, the levels of GSH and GR were also decreased following zinc supplementation to DMH treated rats. Well-differentiated signs of dysplasia were evident in colonic tissue sections by DMH administration alone. However, zinc treatment to DMH treated rats greatly restored normalcy in the colonic histoarchitecture, with no apparent signs of neoplasia. EDXRF studies revealed a significant decrease in tissue concentrations of zinc in the colon following DMH treatment, which upon zinc supplementation were recovered to near normal levels. In conclusion, the results of this study suggest that zinc has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats induced by DMH.

  16. Sewage sludge does not induce genotoxicity and carcinogenesis.

    PubMed

    Silva, Paula Regina Pereira; Barbisan, Luis Fernando; Dagli, Maria Lúcia Zaidan; Saldiva, Paulo Hilário Nascimento

    2012-07-01

    Through a series of experiments, the genotoxic/mutagenic and carcinogenic potential of sewage sludge was assessed. Male Wistar rats were randomly assigned to four groups: Group 1 - negative control; Group 2 - liver carcinogenesis initiated by diethylnitrosamine (DEN; 200 mg/kg i.p.); Group 3 and G4-liver carcinogenesis initiated by DEN and fed 10,000 ppm or 50,000 ppm of sewage sludge. The animals were submitted to a 70% partial hepatectomy at the 3(rd) week. Livers were processed for routine histological analysis and immunohistochemistry, in order to detect glutathione S-transferase positive altered hepatocyte foci (GST-P(+) AHF). Peripheral blood samples for the comet assay were obtained from the periorbital plexus immediately prior to sacrificing. Polychromatic erythrocytes (PCEs) were analyzed in femoral bone-marrow smears, and the frequencies of those micronucleated (MNPCEs) registered. There was no sewage-sludge-induced increase in frequency of either DNA damage in peripheral blood leucocytes, or MNPCEs in the femoral bone marrow. Also, there was no increase in the levels of DNA damage, in the frequency of MNPCEs, and in the development of GST-P AHF when compared with the respective control group.

  17. Chemically induced skin carcinogenesis: Updates in experimental models (Review)

    PubMed Central

    NEAGU, MONICA; CARUNTU, CONSTANTIN; CONSTANTIN, CAROLINA; BODA, DANIEL; ZURAC, SABINA; SPANDIDOS, DEMETRIOS A.; TSATSAKIS, ARISTIDIS M.

    2016-01-01

    Skin cancer is one of the most common malignancies affecting humans worldwide, and its incidence is rapidly increasing. The study of skin carcinogenesis is of major interest for both scientific research and clinical practice and the use of in vivo systems may facilitate the investigation of early alterations in the skin and of the mechanisms involved, and may also lead to the development of novel therapeutic strategies for skin cancer. This review outlines several aspects regarding the skin toxicity testing domain in mouse models of chemically induced skin carcinogenesis. There are important strain differences in view of the histological type, development and clinical evolution of the skin tumor, differences reported decades ago and confirmed by our hands-on experience. Using mouse models in preclinical testing is important due to the fact that, at the molecular level, common mechanisms with human cutaneous tumorigenesis are depicted. These animal models resemble human skin cancer development, in that genetic changes caused by carcinogens and pro-inflammatory cytokines, and simultaneous inflammation sustained by pro-inflammatory cytokines and chemokines favor tumor progression. Drugs and environmental conditions can be tested using these animal models. keeping in mind the differences between human and rodent skin physiology. PMID:26986013

  18. Sewage sludge does not induce genotoxicity and carcinogenesis

    PubMed Central

    Silva, Paula Regina Pereira; Barbisan, Luis Fernando; Dagli, Maria Lúcia Zaidan; Saldiva, Paulo Hilário Nascimento

    2012-01-01

    Through a series of experiments, the genotoxic/mutagenic and carcinogenic potential of sewage sludge was assessed. Male Wistar rats were randomly assigned to four groups: Group 1 - negative control; Group 2 - liver carcinogenesis initiated by diethylnitrosamine (DEN; 200 mg/kg i.p.); Group 3 and G4-liver carcinogenesis initiated by DEN and fed 10,000 ppm or 50,000 ppm of sewage sludge. The animals were submitted to a 70% partial hepatectomy at the 3rd week. Livers were processed for routine histological analysis and immunohistochemistry, in order to detect glutathione S-transferase positive altered hepatocyte foci (GST-P+ AHF). Peripheral blood samples for the comet assay were obtained from the periorbital plexus immediately prior to sacrificing. Polychromatic erythrocytes (PCEs) were analyzed in femoral bone-marrow smears, and the frequencies of those micronucleated (MNPCEs) registered. There was no sewage-sludge-induced increase in frequency of either DNA damage in peripheral blood leucocytes, or MNPCEs in the femoral bone marrow. Also, there was no increase in the levels of DNA damage, in the frequency of MNPCEs, and in the development of GST-P AHF when compared with the respective control group. PMID:23055806

  19. ETS2 and Twist1 promote invasiveness of Helicobacter pylori-infected gastric cancer cells by inducing Siah2

    PubMed Central

    Das, Lopamudra; Kokate, Shrikant Babanrao; Rath, Suvasmita; Rout, Niranjan; Singh, Shivaram Prasad; Crowe, Sheila Eileen; Mukhopadhyay, Asish K.; Bhattacharyya, Asima

    2016-01-01

    Helicobacter pylori infection is one of the most potent factors leading to gastric carcinogenesis. The seven in absentia homologue (Siah2) is an E3 ubiquitin ligase which has been implicated in various cancers but its role in H. pylori-mediated gastric carcinogenesis has not been established. We investigated the involvement of Siah2 in gastric cancer metastasis which was assessed by invasiveness and migration of H. pylori-infected gastric epithelial cancer cells. Cultured gastric cancer cells (GCCs) MKN45, AGS and Kato III showed significantly induced expression of Siah2, increased invasiveness and migration after being challenged with the pathogen. Siah2-expressing stable cells showed increased invasiveness and migration after H. pylori infection. Siah2 was transcriptionally activated by E26 transformation-specific sequence 2 (ETS2)- and Twist-related protein 1 (Twist1) induced in H. pylori-infected gastric epithelial cells. These transcription factors dose-dependently enhanced the aggressiveness of infected GCCs. Our data suggested that H. pylori-infected GCCs gained cell motility and invasiveness through Siah2 induction. As gastric cancer biopsy samples also showed highly induced expression of ETS2, Twist1 and Siah2 compared with noncancerous gastric tissue, we surmise that ETS2- and Twist1-mediated Siah2 up-regulation has potential diagnostic and prognostic significance and could be targeted for therapeutic purpose. PMID:27048589

  20. The Interplay of LncRNA-H19 and Its Binding Partners in Physiological Process and Gastric Carcinogenesis

    PubMed Central

    Zhang, Li; Zhou, Yuhang; Huang, Tingting; Cheng, Alfred S. L.; Yu, Jun; Kang, Wei; To, Ka Fai

    2017-01-01

    Long non-coding RNA (lncRNA), a novel and effective modulator in carcinogenesis, has become a study hotspot in recent years. The imprinted oncofetal lncRNA H19 is one of the first identified imprinted lncRNAs with a high expression level in embryogenesis but is barely detectable in most tissues after birth. Aberrant alterations of H19 expression have been demonstrated in various tumors, including gastric cancer (GC), implicating a crucial role of H19 in cancer progression. As one of the top malignancies in the world, GC has already become a serious concern to public health with poor prognosis. The regulatory roles of H19 in gastric carcinogenesis have been explored by various research groups, which leads to the development of GC therapy. This review comprehensively summarizes the current knowledge of H19 in tumorigenesis, especially in GC pathogenesis, with emphasis on the underneath molecular mechanisms depicted from its functional partners. Furthermore, the accumulated knowledge of H19 will provide better understanding on targeted therapy of GC. PMID:28230721

  1. The Interplay of LncRNA-H19 and Its Binding Partners in Physiological Process and Gastric Carcinogenesis.

    PubMed

    Zhang, Li; Zhou, Yuhang; Huang, Tingting; Cheng, Alfred S L; Yu, Jun; Kang, Wei; To, Ka Fai

    2017-02-20

    Long non-coding RNA (lncRNA), a novel and effective modulator in carcinogenesis, has become a study hotspot in recent years. The imprinted oncofetal lncRNA H19 is one of the first identified imprinted lncRNAs with a high expression level in embryogenesis but is barely detectable in most tissues after birth. Aberrant alterations of H19 expression have been demonstrated in various tumors, including gastric cancer (GC), implicating a crucial role of H19 in cancer progression. As one of the top malignancies in the world, GC has already become a serious concern to public health with poor prognosis. The regulatory roles of H19 in gastric carcinogenesis have been explored by various research groups, which leads to the development of GC therapy. This review comprehensively summarizes the current knowledge of H19 in tumorigenesis, especially in GC pathogenesis, with emphasis on the underneath molecular mechanisms depicted from its functional partners. Furthermore, the accumulated knowledge of H19 will provide better understanding on targeted therapy of GC.

  2. Inhibitory effects of polysaccharides isolated from Phellinus gilvus on benzo(a)pyrene-induced forestomach carcinogenesis in mice

    PubMed Central

    Bae, Jae-Sung; Jang, Kwang-Ho; Yim, Hyunee; Park, Seung-Chun; Jin, Hee-Kyung

    2005-01-01

    AIM: Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study. METHODS: A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4, PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis. RESULTS: In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk. CONCLUSION: Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression. PMID:15641149

  3. Inhibitory effects of polysaccharides isolated from Phellinus gilvus on benzo(a)pyrene-induced forestomach carcinogenesis in mice.

    PubMed

    Bae, Jae-Sung; Jang, Kwang-Ho; Yim, Hyunee; Park, Seung-Chun; Jin, Hee-Kyung

    2005-01-28

    Although polysaccharides from Phellinus mushrooms are a well-known material with anti-tumor properties, there is no information about the effect of polysaccharides from Phellinus gilvus (PG) on tumor. The modulating effect of polysaccharides isolated from PG on the benzo(a)pyrene (BaP)-induced forestomach carcinogenesis in ICR female mice was investigated in this study. A forestomach carcinogenesis model was established in 40 ICR female mice receiving oral administration of BaP for 4 wk. The mice were randomly assigned to 4 groups (10 each). The mice in each group were treated with sterile water or PG for 4 and 8 wk (SW4, PGW4, SW8, and PGW8 groups). Eight or 12 wk after the first dose of BaP, forestomachs were removed for histopathological and RT-PCR analysis. In histopathological changes and RT-PCR analysis, sterile water-treated mice showed significant hyperplasia of the gastric mucosa with a significantly increased expression of mutant p53 mRNA compared to mice treated with PG for 8 wk. Polysaccharides isolated from PG may inhibit BaP-induced forestomach carcinogenesis in mice bydown-regulating mutant p53 expression.

  4. Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression.

    PubMed

    Kim, Yoon Jae; Lee, Jeong Sang; Hong, Kyung Sook; Chung, Jun Won; Kim, Ju Hyun; Hahm, Ki Baik

    2010-08-01

    Colitis-associated cancers arise in the setting of chronic inflammation wherein an "inflammation-dysplasia-carcinoma" sequence prevails. Based on our previous findings in which the proton pump inhibitor could impose significant levels of anti-inflammatory, antiangiogenic, and selective apoptosis induction beyond gastric acid suppression, we investigated whether omeprazole could prevent the development of colitis-associated cancer in a mouse model induced by repeated bouts of colitis. Omeprazole, 10 mg/kg, was given i.p. all through the experimental periods for colitis-associated carcinogenesis. Molecular changes regarding inflammation and carcinogenesis were compared between control groups and colitis-associated cancer groups treated with omeprazole in addition to chemopreventive outcome. Nine of 12 (75.0%) mice in the control group developed multiple colorectal tumors, whereas tumors were noted in only 3 of 12 (25.0%) mice treated with daily injections of omeprazole. The cancer-preventive results of omeprazole treatment was based on significant decreases in the levels of nitric oxide, thiobarbituric acid-reactive substance, and interleukin-6 accompanied with attenuated expressions of tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2. The expressions of matrix metalloproteinase (MMP)-9, MMP-11, and MT1-MMMP were significantly decreased in mice treated with omeprazole in accordance with significant decreases in the number of beta-catenin-accumulated crypts. A significant induction of apoptosis was observed in tumor tissue treated with omeprazole. Omeprazole could block the trophic effect of gastrin in colon epithelial cells. The significant anti-inflammatory, antioxidative, and antimutagenic activities of omeprazole played a cancer-preventive role against colitis-induced carcinogenesis, and our novel in vivo evidence is suggestive of chemopreventive action independent of gastric acid suppression.

  5. Inhibition of autophagy prevents cadmium-induced prostate carcinogenesis.

    PubMed

    Pal, Deeksha; Suman, Suman; Kolluru, Venkatesh; Sears, Sophia; Das, Trinath P; Alatassi, Houda; Ankem, Murali K; Freedman, Jonathan H; Damodaran, Chendil

    2017-06-27

    Cadmium, an established carcinogen, is a risk factor for prostate cancer. Induction of autophagy is a prerequisite for cadmium-induced transformation and metastasis. The ability of Psoralidin (Pso), a non-toxic, orally bioavailable compound to inhibit cadmium-induced autophagy to prevent prostate cancer was investigated. Psoralidin was studied using cadmium-transformed prostate epithelial cells (CTPE), which exhibit high proliferative, invasive and colony forming abilities. Gene and protein expression were evaluated by qPCR, western blot, immunohistochemistry and immunofluorescence. Xenograft models were used to study the chemopreventive effects in vivo. Cadmium-transformed prostate epithelial cells were treated with Pso resulting in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE-1). Psoralidin-treatment of CTPE cells inhibited the expression of Placenta Specific 8, a lysosomal protein essential for autophagosome and autolysosome fusion, which resulted in growth inhibition. Additionally, Pso treatment caused decreased expression of pro-survival signalling proteins, NFκB and Bcl2, and increased expression of apoptotic genes. In vivo, Pso effectively suppressed CTPE xenografts growth, without any observable toxicity. Tumours from Pso-treated animals showed decreased autophagic morphology, mesenchymal markers expression and increased epithelial protein expression. These results confirm that inhibition of autophagy by Pso plays an important role in the chemoprevention of cadmium-induced prostate carcinogenesis.

  6. Geranylgeranylacetone protects guinea pig gastric mucosal cells from gastric stressor-induced apoptosis.

    PubMed

    Takano, Tatsunori; Tsutsumi, Shinji; Tomisato, Wataru; Hoshino, Tatsuya; Tsuchiya, Tomofusa; Mizushima, Tohru

    2002-07-01

    Various stressors induce apoptosis in gastric mucosal cells, which may cause gastric mucosal lesions in vivo. We recently reproduced gastric stressor-induced apoptosis in vitro, using primary cultures of guinea pig gastric mucosal cells. Geranylgeranylacetone is an antiulcer drug with heat-shock protein-inducing properties. The purpose of this study is to examine the effect of geranylgeranylacetone on gastric stressor-induced apoptosis in vitro. Ethanol, hydrogen peroxide, and hydrochloric acid all induced, in a dose-dependent manner, apoptotic DNA fragmentation. Pretreatment of cells with geranylgeranylacetone inhibited the apoptotic DNA fragmentation caused by each of these gastric stressors. Pretreatment of cells with a low concentration of ethanol, a procedure that is also known tb induce heat-shock proteins, made cells resistant to the apoptotic DNA fragmentation. These results suggest that heat-shock proteins could be at least partly involved in the inhibitory effect of geranylgeranylacetone against apoptosis of gastric mucosal cells caused by these gastric stressors.

  7. Iron medication-induced gastric mucosal injury.

    PubMed

    Zhang, Xuchen; Ouyang, Jie; Wieczorek, Rosemary; DeSoto, Fidelina

    2009-01-01

    Severe gastrointestinal erosion, ulcer, necrosis and strictures after an acute iron overdose are well described. However, gastric mucosal injury in patients receiving therapeutic iron has received only scant recognition despite its wide use. We report a case of iron medication-induced gastric mucosal injury in a 76-year-old male who presented with iron deficiency anemia and had been taking ferrous sulfate tablet for 4 years. Esophagogastroduodenoscopy (EGD) revealed a pale, villous appearing flat lesion along the lesser curvature of gastric body. Histopathologic examination of EGD biopsies of the flat lesion showed brown crystalline materials deposited in the lamina propria of gastric mucosa, which was accompanied with fibrosis, chronic inflammation, and foreign body reaction. The crystalline materials were covered and admixed with gastric epithelium. Prussian blue iron stain confirmed that the brown crystalline materials were iron. The iron and hemosiderin accumulation was also seen in cytoplasm of epithelial cells and lumen of fundic gastric glands. The recognition and reporting by pathologists of iron-induced changes in EGD biopsies will alert clinicians to this underrecognized but easily correctable complication by alternative forms of iron therapy, such as liquid preparation.

  8. hsa-miR-29c and hsa-miR-135b differential expression as potential biomarker of gastric carcinogenesis

    PubMed Central

    Vidal, Amanda Ferreira; Cruz, Aline MP; Magalhães, Leandro; Pereira, Adenilson L; Anaissi, Ana KM; Alves, Nélisson CF; Albuquerque, Paulo JBS; Burbano, Rommel MR; Demachki, Samia; Ribeiro-dos-Santos, Ândrea

    2016-01-01

    AIM: To investigate the expression profiles of hsa-miR-29c and hsa-miR-135b in gastric mucosal samples and their values as gastric carcinogenesis biomarkers. METHODS: The expression levels of hsa-miR-29c and hsa-miR-135b in normal gastric mucosa, non-atrophic chronic gastritis, intestinal metaplasia and intestinal-type gastric adenocarcinoma were analysed using quantitative real-time PCR. The difference between hsa-miR-29c and hsa-miR-135b expression profiles in the grouped samples was evaluated by ANOVA and Student’s t-test tests. The results were adjusted for multiple testing by using Bonferroni’s correction. P values ≤ 0.05 were considered statistically significant. To evaluate hsa-miR-29c and hsa-miR-135b expressions as potential biomarkers of gastric carcinogenesis, we performed a receiver operating characteristic curve analysis and the derived area under the curve, and a Categorical Principal Components Analysis. In silico identification of the genetic targets of hsa-miR-29c and hsa-miR-135b was performed using different prediction tools, in order to identify possible genes involved in gastric carcinogenesis. RESULTS: The expression levels of hsa-miR-29c were higher in normal gastric mucosal samples, and decreased progressively in non-atrophic chronic gastritis samples, intestinal metaplasia samples and intestinal-type gastric adenocarcinoma samples. The expression of hsa-miR-29c in the gastric lesions showed that non-atrophic gastritis have an intermediate profile to gastric normal mucosa and intestinal-type gastric adenocarcinoma, and that intestinal metaplasia samples presented an expression pattern similar to that in intestinal-type gastric adenocarcinoma. This microRNA (miRNA) has a good discriminatory accuracy between normal gastric samples and (1) intestinal-type gastric adenocarcinoma; and (2) intestinal metaplasia, and regulates the DMNT3A oncogene. hsa-miR-135b is up-regulated in non-atrophic chronic gastritis and intestinal metaplasia samples

  9. MicroRNA-3178 ameliorates inflammation and gastric carcinogenesis promoted by Helicobacter pylori new toxin, Tip-α, by targeting TRAF3.

    PubMed

    Zou, Meijuan; Wang, Fang; Jiang, Aiqin; Xia, Anliang; Kong, Siya; Gong, Chun; Zhu, Mingxia; Zhou, Xin; Zhu, Jun; Zhu, Wei; Cheng, Wenfang

    2017-04-01

    Helicobacter pylori infection is the main cause of chronic gastritis, peptic ulcer, and gastric cancer. Tip-α is a newly identified carcinogenic factor present in H. pylori. TRAF3 can activate NF-κB by both canonical and noncanonical signaling pathways. In this study, we found that the expression of TRAF3 and NF-κB was upregulated, while microRNA-3178 (miR-3178) was decreased in H. pylori-positive gastric tissues but not in H. pylori-negative tissues. GES-1 cells were incubated with 12.5 μg/mL recombinant Tip-α (rTip-α) in RPMI1640 for 2 hours. After another 24 hours, the supernatant medium was designed as inflammatory-conditioned medium (ICM) and that from the untreated control cells was designed as untreated control medium. The release of proinflammatory cytokines from GES-1 cells and proliferation of gastric cancer cells was determined by ELISA and CCK-8 kits. Cells were transfected with the mimic, inhibitor, negative control of miR-3178, or TRAF3 siRNA control siRNA. The medium was then replaced with RPMI1640, 12.5 μg/mL rTip-α, and collected, and the total cellular RNA and protein were extracted for the following detection. MiR-3178 mimic prevented the increasement of TRAF3 and hence decreased activation of NF-κB signals, whereas miR-3178 inhibitor could not, in GES-1 cells with Tip-α treatment. The condition medium from miR-3178 mimic transfected GES-1 cells could inhibit proliferation and induce apoptosis of inflammation-related gastric cancer cells SGC7901 and MGC803 by decreasing the production of inflammatory cytokines TNF-α and IL-6, which were secreted by GES-1 cells. Taken all together, Tip-α might activate NF-κB to promote inflammation and carcinogenesis by inhibiting miR-3178 expression, which directly targeting TRAF3, during H. pylori infection in gastric mucosal epithelial cells. © 2016 John Wiley & Sons Ltd.

  10. BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer

    PubMed Central

    2010-01-01

    Background The BMI1 oncogene is overexpressed in several human malignancies including gastric cancer. In addition to BMI1, mammalian cells also express Mel-18, which is closely related to BMI1. We have reported that Mel-18 functions as a potential tumor suppressor by repressing the expression of BMI1 and consequent downregulation of activated AKT in breast cancer cells. However, the mechanisms of BMI1 overexpression and the role of Mel-18 in other cancers are still not clear. The purpose of this study is to investigate the role of BMI1 and Mel-18 in gastric cancer. Results BMI1 was found to be overexpressed in gastric cancer cell lines and gastric tumors. Overexpression of BMI1 correlated with advanced clinical stage and lymph node metastasis; while the expression of Mel-18 negatively correlated with BMI1. BMI1 but not Mel-18 was found to be an independent prognostic factor. Downregulation of BMI1 by Mel-18 overexpression or knockdown of BMI1 expression in gastric cancer cell lines led to upregulation of p16 (p16INK4a or CDKN2A) in p16 positive cell lines and reduction of phospho-AKT in both p16-positive and p16-negative cell lines. Downregulation of BMI1 was also accompanied by decreased transformed phenotype and migration in both p16- positive and p16-negative gastric cancer cell lines. Conclusions In the context of gastric cancer, BMI1 acts as an oncogene and Mel-18 functions as a tumor suppressor via downregulation of BMI1. Mel-18 and BMI1 may regulate tumorigenesis, cell migration and cancer metastasis via both p16- and AKT-dependent growth regulatory pathways. PMID:20170541

  11. BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer.

    PubMed

    Zhang, Xiao-Wei; Sheng, Ya-Ping; Li, Qian; Qin, Wei; Lu, You-Wei; Cheng, Yu-Fan; Liu, Bing-Ya; Zhang, Feng-Chun; Li, Jin; Dimri, Goberdhan P; Guo, Wei-Jian

    2010-02-21

    The BMI1 oncogene is overexpressed in several human malignancies including gastric cancer. In addition to BMI1, mammalian cells also express Mel-18, which is closely related to BMI1. We have reported that Mel-18 functions as a potential tumor suppressor by repressing the expression of BMI1 and consequent downregulation of activated AKT in breast cancer cells. However, the mechanisms of BMI1 overexpression and the role of Mel-18 in other cancers are still not clear. The purpose of this study is to investigate the role of BMI1 and Mel-18 in gastric cancer. BMI1 was found to be overexpressed in gastric cancer cell lines and gastric tumors. Overexpression of BMI1 correlated with advanced clinical stage and lymph node metastasis; while the expression of Mel-18 negatively correlated with BMI1. BMI1 but not Mel-18 was found to be an independent prognostic factor. Downregulation of BMI1 by Mel-18 overexpression or knockdown of BMI1 expression in gastric cancer cell lines led to upregulation of p16 (p16INK4a or CDKN2A) in p16 positive cell lines and reduction of phospho-AKT in both p16-positive and p16-negative cell lines. Downregulation of BMI1 was also accompanied by decreased transformed phenotype and migration in both p16- positive and p16-negative gastric cancer cell lines. In the context of gastric cancer, BMI1 acts as an oncogene and Mel-18 functions as a tumor suppressor via downregulation of BMI1. Mel-18 and BMI1 may regulate tumorigenesis, cell migration and cancer metastasis via both p16- and AKT-dependent growth regulatory pathways.

  12. Role of Viral miRNAs and Epigenetic Modifications in Epstein-Barr Virus-Associated Gastric Carcinogenesis.

    PubMed

    Giudice, Aldo; D'Arena, Giovanni; Crispo, Anna; Tecce, Mario Felice; Nocerino, Flavia; Grimaldi, Maria; Rotondo, Emanuela; D'Ursi, Anna Maria; Scrima, Mario; Galdiero, Massimiliano; Ciliberto, Gennaro; Capunzo, Mario; Franci, Gianluigi; Barbieri, Antonio; Bimonte, Sabrina; Montella, Maurizio

    2016-01-01

    MicroRNAs are short (21-23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses. The vast majority of viral miRNAs are encoded by the herpesviruses family. These DNA viruses including Epstein-Barr virus encode their own miRNAs and/or manipulate the expression of cellular miRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs.

  13. Role of Viral miRNAs and Epigenetic Modifications in Epstein-Barr Virus-Associated Gastric Carcinogenesis

    PubMed Central

    Giudice, Aldo; D'Arena, Giovanni; Crispo, Anna; Tecce, Mario Felice; Nocerino, Flavia; Grimaldi, Maria; Rotondo, Emanuela; D'Ursi, Anna Maria; Scrima, Mario; Galdiero, Massimiliano; Ciliberto, Gennaro; Capunzo, Mario; Franci, Gianluigi; Barbieri, Antonio; Bimonte, Sabrina; Montella, Maurizio

    2016-01-01

    MicroRNAs are short (21–23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses. The vast majority of viral miRNAs are encoded by the herpesviruses family. These DNA viruses including Epstein-Barr virus encode their own miRNAs and/or manipulate the expression of cellular miRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs. PMID:26977250

  14. Evidence of cell fusion in carcinogen-induced mice gastric carcinoma.

    PubMed

    Yan, Yongjia; Hsu, Yiling; He, Xianghui; Lu, Ning; Wei, Wei; Zhang, Zhixiang; Zhu, Liwei

    2015-07-01

    The role of bone marrow-derived cells in gastric cancer formation was not fully understood. In this study, bone marrow from female green fluorescent protein transgenic mice was transplanted into male wild-type mice to generate sex-mismatched chimeric mice. The chimeric mice were treated with carcinogen to induce gastric cancer. At time of sacrifice, 18.2 % (2/11) of mice showed severe dysplasia and 25 % (3/12) of mice successfully induced with cancer. Fluorescence in situ hybridization results showed that bone marrow-derived cells participated in renewal of gastric mucosa and cell fusion was observed in both precancerous lesions and adenocarcinoma, but no sign of fusion was observed in squamous cell carcinoma. Our findings suggest that bone marrow-derived cells participate in renewal of gastric mucosa during chronic damage and might have acquired the phenotype of gastric epithelial cells through cell fusion. Fusion between gastric epithelial cells and bone marrow-derived cells was involved in increased carcinogenesis.

  15. Transgenic cyclooxygenase-2 expression and high salt enhanced susceptibility to chemical-induced gastric cancer development in mice.

    PubMed

    Leung, Wai K; Wu, Kai-chun; Wong, Christine Y P; Cheng, Alfred S L; Ching, Arthur K K; Chan, Anthony W H; Chong, Wilson W S; Go, Minnie Y Y; Yu, Jun; To, Ka-Fai; Wang, Xin; Chui, Y L; Fan, D M; Sung, Joseph J Y

    2008-08-01

    Cyclooxoygenase (COX)-2 overexpression is involved in gastric carcinogenesis. While high-salt intake is a known risk factor for gastric cancer development, we determined the effects of high salt on gastric chemical carcinogenesis in COX-2 transgenic (TG) mice. COX-2 TG mice were developed in C57/BL6 strain using the full-length human cox-2 complementary DNA construct. Six-week-old COX-2 TG and wild-type (WT) littermates were randomly allocated to receive alternate week of N-methyl-N-nitrosourea (MNU, 240 p.p.m.) in drinking water or control for 10 weeks. Two groups of mice were further treated with 10% NaCl during the initial 10 weeks. All mice were killed at the end of week 50. Both forced COX-2 overexpression and high-salt intake significantly increased the frequency of gastric cancer development in mice as compared with WT littermates treated with MNU alone. However, no additive effect was observed on the combination of high salt and COX-2 expression. We further showed that MNU and high-salt treatment increased chronic inflammatory infiltrates and induced prostaglandin E(2) (PGE(2)) production in the non-cancerous stomach. Whereas high-salt treatment markedly increased the expression of inflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-1 beta and IL-6) in the gastric mucosa, COX-2 overexpression significantly altered the cell kinetics in the MNU-induced gastric cancer model. In conclusion, both high salt and COX-2 overexpression promote chemical-induced gastric carcinogenesis, possibly related to chronic inflammation, induction of PGE(2), disruption of cell kinetics and induction of inflammatory cytokines.

  16. LncRNA-RMRP promotes carcinogenesis by acting as a miR-206 sponge and is used as a novel biomarker for gastric cancer.

    PubMed

    Shao, Yongfu; Ye, Meng; Li, Qier; Sun, Weiliang; Ye, Guoliang; Zhang, Xinjun; Yang, Yunben; Xiao, Bingxiu; Guo, Junming

    2016-06-21

    Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis. However, the mechanisms of most lncRNAs in cancers are largely unknown. Because the RNA component of mitochondrial RNA processing endoribonuclease (RMRP) is one of the dysregulated lncRNAs in gastric cancer, this study explored its molecular mechanisms in carcinogenesis. RMRP levels in 792 tissues, plasma and gastric juices from patients with various stages of gastric tumorigenesis were analyzed by quantitative reverse transcription-polymerase chain reaction. Overexpression and RNA interference were used to manipulate RMRP expression by RMRP expression vector and small interfering RNAs, respectively. Its mechanisms were evaluated by flow cytometry, real-time cell analysis, plate colony formation assays, and xenograft models. RMRP levels in tissue, plasma and gastric juices from patients with gastric cancer were significantly different from those from controls. Its levels were significantly associated with Borrmann type and metastasis. Plasma and gastric juice RMRP had higher sensitivity and specificity than commonly used markers (such as carcinoembryonic antigen and carbohydrate antigen 19-9). Knockdown of RMRP significantly inhibited cell proliferation in vitro and in vivo, whereas overexpression of RMRP promoted cell growth. Acting as a miR-206 sponge, RMRP modulated cell cycle by regulating Cyclin D2 expression. RMRP plays a crucial role in gastric cancer occurrence and can be used as a novel biomarker for gastric cancer.

  17. The Mongolian Gerbil: A Robust Model of Helicobacter pylori-Induced Gastric Inflammation and Cancer.

    PubMed

    Noto, Jennifer M; Romero-Gallo, Judith; Piazuelo, M Blanca; Peek, Richard M

    2016-01-01

    The Mongolian gerbil is an efficient, robust, and cost-effective rodent model that recapitulates many features of H. pylori-induced gastric inflammation and carcinogenesis in humans, allowing for targeted investigation of the bacterial determinants and environmental factors and, to a lesser degree, host constituents that govern H. pylori-mediated disease. This chapter discusses means through which the Mongolian gerbil model has been used to define mechanisms of H. pylori-inflammation and cancer as well as the current materials and methods for utilizing this model of microbially induced disease.

  18. Rebamipide-induced downregulation of phospholipase D inhibits inflammation and proliferation in gastric cancer cells

    PubMed Central

    Kang, Dong Woo; Min, Gyesik; Park, Do Yoon; Hong, Ki Whan

    2010-01-01

    Rebamipide a gastroprotective drug, is clinically used for the treatment of gastric ulcers and gastritis, but its actions on gastric cancer are not clearly understood. Phospholipase D (PLD) is overexpressed in various types of cancer tissues and has been implicated as a critical factor in inflammation and carcinogenesis. However, whether rebamipide is involved in the regulation of PLD in gastric cancer cells is not known. In this study, we showed that rebamipide significantly suppressed the expression of both PLD1 and PLD2 at a transcriptional level in AGS and MKN-1 gastric cancer cells. Downregulation of PLD expression by rebamipide inhibited its enzymatic activity. In addition, rebamipide inhibited the transactivation of nuclear factor kappa B (NFκB), which increased PLD1 expression. Rebamipide or PLD knockdown significantly suppressed the expression of genes involved in inflammation and proliferation and inhibited the proliferation of gastric cancer cells. In conclusion, rebamipide-induced downregulation of PLD may contribute to the inhibition of inflammation and proliferation in gastric cancer. PMID:20625243

  19. [Radiation carcinogenesis].

    PubMed

    Hosoi, Yoshio

    2013-11-01

    Misrepair of DNA damage induced by ionizing radiation is a potential cause of carcinogenesis following exposure to radiation. Radiation exposure increases the incidence of the same types of mutations that occur spontaneously in a given population. A high incidence of DNA double-strand breaks is characteristic of damage by ionizing radiation compared with those induced by other environmental mutagens. In China, residents living in areas with high level background radiation(6mSv/y) had a significantly higher frequency of dicentric and ring chromosomes compared to that for the residents living in the control areas(2mSv/y). Radiation-associated increases in risk were seen for most sites. Gender-averaged excess absolute risk rates estimated at age 70, after exposure at age 30, differ in the sites, and the risks of gastric cancer, breast cancer, colon cancer, and lung cancer were highly increased, in that order. Latent periods for the development of leukemia and thyroid cancer after radiation exposure at ages younger than 18 were shorter compared to those for other solid cancers.

  20. PROPICONAZOLE-INDUCED CARCINOGENESIS: ROLE OF OXIDATIVE STRESS

    EPA Science Inventory

    Propiconazole is a systemic foliar fungicide with a broad range of activity. Rodents fed with propiconazole at high dose resulted in diminished body weight, increased liver weight of adults and pups, and eventually liver carcinogenesis. In order to unravel the toxic processes inv...

  1. PROPICONAZOLE-INDUCED CARCINOGENESIS: ROLE OF OXIDATIVE STRESS

    EPA Science Inventory

    Propiconazole is a systemic foliar fungicide with a broad range of activity. Rodents fed with propiconazole at high dose resulted in diminished body weight, increased liver weight of adults and pups, and eventually liver carcinogenesis. In order to unravel the toxic processes inv...

  2. Cancer stem cell hypothesis and gastric carcinogenesis: Experimental evidence and unsolved questions

    PubMed Central

    Rocco, Alba; Compare, Debora; Nardone, Gerardo

    2012-01-01

    Traditionally, the clonal evolution model has been used to explain gastric cancer (GC) growth dynamics. According to this model, GC cells result from multiple mutations over time resulting in a population of continually diversifying cells. This heterogeneity enables the survival of different clones under particular conditions allowing growth at metastatic locations or resistance to chemotherapeutics. Cancer stem cell (CSC) theory completely overturns this traditional understanding of cancer suggesting that only CSCs can self-renew and promote tumor growth. CSCs are relatively refractory to conventional therapies, thus explaining why anti-cancer therapies are far from curative and why relapses of cancer are frequent. The identification of the CSC component of a tumor might, thus, open new therapeutic perspective based on the selective targeting of this small population of cells. In this review we examine the current scientific evidence supporting the existence of CSC in gastric tumors and analyze the main unsolved questions of this difficult field of cancer research. PMID:22468184

  3. Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro

    PubMed Central

    Bessède, Emilie; Molina, Silvia; Amador, Luis Acuña; Dubus, Pierre; Staedel, Cathy; Chambonnier, Lucie; Buissonnière, Alice; Sifré, Elodie; Giese, Alban; Bénéjat, Lucie; Rousseau, Benoît; Costet, Pierre; Sacks, David B.; Mégraud, Francis; Varon, Christine

    2016-01-01

    Helicobacter pylori infection is responsible for gastric carcinogenesis but host factors are also implicated. IQGAP1, a scaffolding protein of the adherens junctions interacting with E-cadherin, regulates cellular plasticity and proliferation. In mice, IQGAP1 deficiency leads to gastric hyperplasia. The aim of this study was to elucidate the consequences of IQGAP1 deletion on H. pylori-induced gastric carcinogenesis. Transgenic mice deleted for iqgap1 and WT littermates were infected with Helicobacter sp., and histopathological analyses of the gastric mucosa were performed. IQGAP1 and E-cadherin expression was evaluated in gastric tissues and in gastric epithelial cell lines in response to H. pylori infection. The consequences of IQGAP1 deletion on gastric epithelial cell behaviour and on the acquisition of cancer stem cell (CSC)-like properties were evaluated. After one year of infection, iqgap1+/- mice developed more preneoplastic lesions and up to 8 times more gastro-intestinal neoplasia (GIN) than WT littermates. H. pylori infection induced IQGAP1 and E-cadherin delocalization from cell-cell junctions. In vitro, knock-down of IQGAP1 favoured the acquisition of a mesenchymal phenotype and CSC-like properties induced by H. pylori infection. Our results indicate that alterations in IQGAP1 signalling promote the emergence of CSCs and gastric adenocarcinoma development in the context of an H. pylori infection. PMID:27729612

  4. Biochemical changes induced by Campylobacter pylori in the gastric juice.

    PubMed

    Andreica, V; Suciu, A; Dumitraşcu, D; Drăghici, A; Pascu, O; Suciu, M; Ban, A

    1990-01-01

    The biochemical changes induced in the gastric juice by the presence of Campylobacter pylori (CP) were followed up in 151 patients with various gastric and duodenal diseases. The diagnosis of CP infection was made by the urease test. In the presence of CP urea decreased in the gastric juice and ammonia increased. The sialic acid, fucose and hexoses, glucide components of the mucus glycoproteins dissolved in the gastric juice, underwent no change in the presence of CP. The hexosamines in the gastric mucus increased significantly in CP patients. Urease activity is present in the gastric juice even in the absence of CP, probably due to other microorganisms present in the human stomach. This does not exclude the use of the urease test for the diagnosis of CP infection. However the test can only be used in the bioptically removed gastric mucosa samples, not in the gastric juice.

  5. Helicobacter pylori induces cell migration and invasion through casein kinase 2 in gastric epithelial cells.

    PubMed

    Lee, Yeo Song; Lee, Do Yeon; Yu, Da Yeon; Kim, Shin; Lee, Yong Chan

    2014-12-01

    Chronic infection with Helicobacter pylori (H. pylori) is causally linked with gastric carcinogenesis. Virulent H. pylori strains deliver bacterial CagA into gastric epithelial cells. Induction of high motility and an elongated phenotype is considered to be CagA-dependent process. Casein kinase 2 plays a critical role in carcinogenesis through signaling pathways related to the epithelial mesenchymal transition. This study was aimed to investigate the effect of H. pylori infection on the casein kinase 2-mediated migration and invasion in gastric epithelial cells. AGS or MKN28 cells as human gastric epithelial cells and H. pylori strains Hp60190 (ATCC 49503, CagA(+)) and Hp8822 (CagA(-)) were used. Cells were infected with H. pylori at multiplicity of infection of 100 : 1 for various times. We measured in vitro kinase assay to examine casein kinase 2 activity and performed immunofluorescent staining to observe E-cadherin complex. We also examined β-catenin transactivation through promoter assay and MMP7 expression by real-time PCR and ELISA. H. pylori upregulates casein kinase 2 activity and inhibition of casein kinase 2 in H. pylori-infected cells profoundly suppressed cell invasiveness and motility. We confirmed that casein kinase 2 mediates membranous α-catenin depletion through dissociation of the α-/β-catenin complex in H. pylori-infected cells. We also found that H. pylori induces β-catenin nuclear translocation and increases MMP7 expressions mediated through casein kinase 2. We show for the first time that CagA(+) H. pylori upregulates cellular invasiveness and motility through casein kinase 2. The demonstration of a mechanistic interplay between H. pylori and casein kinase 2 provides important insights into the role of CagA(+) H. pylori in the gastric cancer invasion and metastasis. © 2014 John Wiley & Sons Ltd.

  6. Virus Carcinogenesis

    DTIC Science & Technology

    1961-01-01

    viruses are capable of inducing cancer, it is obvious that virus carcinogenesis cannot be considered in an isolated fashion, without some reference to...intradermal inoculations of vaccinia virus . One of the viruses most widely investigated with respect to quantitative dose- response relationships is the...than the rule. Figure 6 shows the type of deviation most commonly observed with viruses of infectious diseases. VIRUS CARCINOGENESIS 131 It is a

  7. Green tea catechin extract in intervention of chronic breast cell carcinogenesis induced by environmental carcinogens.

    PubMed

    Rathore, Kusum; Wang, Hwa-Chain Robert

    2012-03-01

    Sporadic breast cancers are mainly attributable to long-term exposure to environmental factors, via a multi-year, multi-step, and multi-path process of tumorigenesis involving cumulative genetic and epigenetic alterations in the chronic carcinogenesis of breast cells from a non-cancerous stage to precancerous and cancerous stages. Epidemiologic and experimental studies have suggested that green tea components may be used as preventive agents for breast cancer control. In our research, we have developed a cellular model that mimics breast cell carcinogenesis chronically induced by cumulative exposures to low doses of environmental carcinogens. In this study, we used our chronic carcinogenesis model as a target system to investigate the activity of green tea catechin extract (GTC) at non-cytotoxic levels in intervention of cellular carcinogenesis induced by cumulative exposures to pico-molar 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P). We identified that GTC, at a non-cytotoxic, physiologically achievable concentration of 2.5 µg/mL, was effective in suppressing NNK- and B[a]P-induced cellular carcinogenesis, as measured by reduction of the acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, increased cell mobility, and acinar-conformational disruption. We also detected that intervention of carcinogen-induced elevation of reactive oxygen species (ROS), increase of cell proliferation, activation of the ERK pathway, DNA damage, and changes in gene expression may account for the mechanisms of GTC's preventive activity. Thus, GTC may be used in dietary and chemoprevention of breast cell carcinogenesis associated with long-term exposure to low doses of environmental carcinogens.

  8. Gastrin and Gastric Cancer

    PubMed Central

    Waldum, Helge L.; Sagatun, Liv; Mjønes, Patricia

    2017-01-01

    Gastric cancer although occurring in reduced frequency is still an important disease, partly because of the bad prognosis when occurring in western countries. This decline in occurrence may mainly be due to the reduced prevalence of Helicobacter pylori (Hp) infection, which is the most important cause of gastric cancer. There exist many different pathological classifications of gastric carcinomas, but the most useful seems to be the one by Lauren into intestinal and diffuse types since these types seldom transform into the other and also have different epidemiology. During the nearly 30 years that have passed since the groundbreaking description of Hp as the cause of gastritis and gastric cancer, a continuous search for the mechanism by which Hp infection causes gastric cancer has been done. Interestingly, it is mainly atrophic gastritis of the oxyntic mucosa that predisposes to gastric cancer possibly by inducing hypoacidity and hypergastrinemia. There are many arguments in favor of an important role of gastrin and its target cell, the enterochromaffin-like cell, in gastric carcinogenesis. The role of gastrin in gastric carcinogenesis implies caution in the long-term treatment with inhibitors of gastric acid secretion inducing secondary hypergastrinemia, in a common disease like gastroesophageal reflux disease. PMID:28144230

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

    PubMed

    Correa, Pelayo; Piazuelo, M Blanca

    2012-01-01

    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.

  10. APOPTOSIS AND PROLIFERATION DURING DICHLOROACETIC ACID (DCA) INDUCED HEPTACELLULAR CARCINOGENESIS IN THE F344 MALE RAT

    EPA Science Inventory

    Apoptosis and Proliferation During DicWoroacetic Acid (DCA) Induced Hepatocellular
    Carcinogenesis in the F344 Male Rat

    Chlorine, introduced into public drinking \\\\'ater supplies for disinfection, can react with organic compounds in surface waters to form toxic by-prod...

  11. APOPTOSIS AND PROLIFERATION DURING DICHLOROACETIC ACID (DCA) INDUCED HEPTACELLULAR CARCINOGENESIS IN THE F344 MALE RAT

    EPA Science Inventory

    Apoptosis and Proliferation During DicWoroacetic Acid (DCA) Induced Hepatocellular
    Carcinogenesis in the F344 Male Rat

    Chlorine, introduced into public drinking \\\\'ater supplies for disinfection, can react with organic compounds in surface waters to form toxic by-prod...

  12. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice.

    PubMed

    Arbeit, J M; Howley, P M; Hanahan, D

    1996-04-02

    High-risk human papillomaviruses (HPVs), including type 16, have been identified as factors in cervical carcinogenesis. However, the presence and expression of the virus per se appear to be insufficient for carcinogenesis. Rather, cofactors most likely are necessary in addition to viral gene expression to initiate neoplasia. One candidate cofactor is prolonged exposure to sex hormones. To examine the possible effects of estrogen on HPV-associated neoplasia, we treated transgenic mice expressing the oncogenes of HPV16 under control of the human keratin-14 promoter (K14-HPV16 transgenic mice) and nontransgenic control mice with slow release pellets of 17beta-estradiol. Squamous carcinomas developed in a multistage pathway exclusively in the vagina and cervix of K14-HPV16 transgenic mice. Estrogen-induced carcinogenesis was accompanied by an incremental increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-HPV16 mice. Expression of the HPV transgenes in untreated transgenic mice was detectable only during estrus; estrogen treatment resulted in transgene expression that was persistent but not further upregulated, remaining at low levels at all stages of carcinogenesis. The data demonstrate a novel mechanism of synergistic cooperation between chronic estrogen exposure and the oncogenes of HPV16 that coordinates squamous carcinogenesis in the female reproductive tract of K14-HPV16 transgenic mice.

  13. Distension-Induced Gastric Contraction is Attenuated in an Experimental Model of Gastric Restraint

    PubMed Central

    Lu, Xiao; Guo, Xiaomei; Mattar, Samer G.; Navia, Jose A.

    2010-01-01

    Background Gastric distension has important implications for motility and satiety. The hypothesis of this study was that distension affects the amplitude and duration of gastric contraction and that these parameters are largely mediated by efferent vagus stimulation. Methods A novel isovolumic myograph was introduced to test these hypotheses. The isovolumic myograph isolates the stomach and records the pressure generated by the gastric contraction under isovolumic conditions. Accordingly, the phasic changes of gastric contractility can be documented. A group of 12 rats were used under in vivo conditions and isolated ex vivo conditions and with two different gastric restraints (small and large) to determine the effect of degree of restraint. Results The comparison of the in vivo and ex vivo contractility provided information on the efferent vagus mediation of gastric contraction, i.e., the in vivo amplitude and duration reached maximum of 12.6 ± 2.7 mmHg and 19.8 ± 5.6 s in contrast to maximum of 5.7 ± 0.9 mmHg and 7.3 ± 1.3 s in ex vivo amplitude and duration, respectively. The comparison of gastric restraint and control groups highlights the role of distension on in vivo gastric contractility. The limitation of gastric distension by restraint drastically reduced the maximal amplitude to below 2.9 ± 0.2 mmHg. Conclusions The results show that distension-induced gastric contractility is regulated by both central nervous system and local mechanisms with the former being more substantial. Furthermore, the gastric restraint significantly attenuates gastric contractility (decreased amplitude and shortened duration of contraction) which is mediated by the efferent vagus activation. These findings have important implications for gastric motility and physiology and may improve our understanding of satiety. PMID:20706803

  14. Heterochromatinization as a Potential Mechanism of Nickel-Induced Carcinogenesis

    PubMed Central

    Ellen, Thomas P.; Kluz, Thomas; Harder, Mark E.; Xiong, Judy; Costa, Max

    2009-01-01

    Epigenetics refers to heritable patterns of gene expression that do not depend on alterations of the genomic DNA sequence. Nickel compounds have demonstrated carcinogenicity without any associated mutagenesis, suggesting that its mechanism of carcinogenesis is epigenetic in nature. One such potential mechanism is the heterochromatinization of chromatin within a region of the genome containing a gene sequence, inhibiting any further molecular interactions with that underlying gene sequence and effectively inactivating that gene. We report here the observation, by atomic force microscopy and circular dichroism spectropolarimetry, that nickel ion (Ni2+) condenses chromatin to a greater extent than the natural divalent cation of the cell, magnesium ion (Mg2+). In addition, we use a model experimental system that incorporates a transgene, the bacterial xanthine guanine phosphoribosyl transferase gene (gpt) differentially near to, and far away from, a heterochromatic region of the genome, in two cell lines, the Chinese hamster V79-derived G12 and G10 cells, respectively, to demonstrate by DNase I protection assay that nickel treatement protects the gpt gene sequence from DNase I exonuclease digestion in the G12 cells, but not in the G10 cells. We conclude that condensation of chromatin by nickel is a potential mechanism of nickel-mediated gene regulation. PMID:19338343

  15. Dual preventive benefits of iron elimination by desferal in asbestos-induced mesothelial carcinogenesis.

    PubMed

    Jiang, Li; Chew, Shan-Hwu; Nakamura, Kosuke; Ohara, Yuuki; Akatsuka, Shinya; Toyokuni, Shinya

    2016-07-01

    Asbestos-induced mesothelial carcinogenesis is currently a profound social issue due to its extremely long incubation period and high mortality rate. Therefore, procedures to prevent malignant mesothelioma in people already exposed to asbestos are important. In previous experiments, we established an asbestos-induced rat peritoneal mesothelioma model, which revealed that local iron overload is a major cause of pathogenesis and that the induced genetic alterations are similar to human counterparts. Furthermore, we showed that oral administration of deferasirox modified the histology from sarcomatoid to the more favorable epithelioid subtype. Here, we used i.p. administration of desferal to evaluate its effects on asbestos-induced peritoneal inflammation and iron deposition, as well as oxidative stress. Nitrilotriacetate was used to promote an iron-catalyzed Fenton reaction as a positive control. Desferal significantly decreased peritoneal fibrosis, iron deposition, and nuclear 8-hydroxy-2'-deoxyguanosine levels in mesothelial cells, whereas nitrilotriacetate significantly increased all of them. Desferal was more effective in rat peritoneal mesothelial cells to counteract asbestos-induced cytotoxicity than in murine macrophages (RAW264.7). Furthermore, rat sarcomatoid mesothelioma cells were more dependent on iron for proliferation than rat peritoneal mesothelial cells. Because inflammogenicity of a fiber is proportionally associated with subsequent mesothelial carcinogenesis, iron elimination from the mesothelial environment can confer dual merits for preventing asbestos-induced mesothelial carcinogenesis by suppressing inflammation and mesothelial proliferation simultaneously. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  16. Resveratrol inhibits estrogen-induced breast carcinogenesis through induction of NRF2-mediated protective pathways

    PubMed Central

    Singh, Bhupendra; Shoulson, Rivka; Chatterjee, Anwesha; Ronghe, Amruta; Bhat, Nimee K.; Dim, Daniel C.; Bhat, Hari K.

    2014-01-01

    The importance of estrogens in the etiology of breast cancer is widely recognized. Estrogen-induced oxidative stress has been implicated in this carcinogenic process. Resveratrol (Res), a natural antioxidant phytoestrogen has chemopreventive effects against a variety of illnesses including cancer. The objective of the present study was to characterize the mechanism(s) of Res-mediated protection against estrogen-induced breast carcinogenesis. Female August Copenhagen Irish rats were treated with 17β-estradiol (E2), Res and Res + E2 for 8 months. Cotreatment of rats with Res and E2 inhibited E2-mediated proliferative changes in mammary tissues and significantly increased tumor latency and reduced E2-induced breast tumor development. Resveratrol treatment alone or in combination with E2 significantly upregulated expression of nuclear factor erythroid 2-related factor 2 (NRF2) in mammary tissues. Expression of NRF2-regulated antioxidant genes NQO1, SOD3 and OGG1 that are involved in protection against oxidative DNA damage was increased in Res- and Res + E2-treated mammary tissues. Resveratrol also prevented E2-mediated inhibition of detoxification genes AOX1 and FMO1. Inhibition of E2-mediated alterations in NRF2 promoter methylation and expression of NRF2 targeting miR-93 after Res treatment indicated Res-mediated epigenetic regulation of NRF2 during E2-induced breast carcinogenesis. Resveratrol treatment also induced apoptosis and inhibited E2-mediated increase in DNA damage in mammary tissues. Increased apoptosis and decreased DNA damage, cell migration, colony and mammosphere formation in Res- and Res + E2-treated MCF-10A cells suggested a protective role of Res against E2-induced mammary carcinogenesis. Small-interfering RNA-mediated silencing of NRF2 inhibited Res-mediated preventive effects on the colony and mammosphere formation. Taken together, these results suggest that Res inhibits E2-induced breast carcinogenesis via induction of NRF2-mediated protective

  17. Vection-induced gastric dysrhythmias and motion sickness

    NASA Technical Reports Server (NTRS)

    Koch, K. L.; Stern, R. M.

    1986-01-01

    Gastric electrical and mechanical activity during vection-induced motion sickness was investigated. The contractile events of the antrum and gastric myoelectric activity in healthy subjects exposed to vection were measured simultaneously. Symptomatic and myoelectric responses of subjects with vagotomy and gastric resections during vection stimuli were determined. And laboratory based computer systems for analysis of the myoelectric signal were developed. Gastric myoelectric activity was recorded from cutaneous electrodes, i.e., electrogastrograms (EGGs), and antral contractions were measured with intraluminal pressure transducers. Vection was induced by a rotating drum. gastric electromechanical activity was recorded during three periods: 15 min baseline, 15 min drum rotation (vection), and 15 to 30 min recovery. Preliminary results showed that catecholamine responses in nauseated versus symptom-free subjects were divergent and pretreatment with metoclopramide HC1 (Reglan) prevented vection-induced nausea and reduced tachygastrias in two previously symptomatic subjects.

  18. p38 MAP Kinase Plays a Functional Role in UVB-Induced Mouse Skin Carcinogenesis

    PubMed Central

    Dickinson, Sally E.; Olson, Erik R.; Zhang, Jack; Cooper, Simon J.; Melton, Tania; Criswell, P. Jane; Casanova, Ana; Dong, Zigang; Hu, Chengcheng; Saboda, Kathylynn; Jacobs, Elizabeth T.; Alberts, David S.; Bowden, G. Tim

    2010-01-01

    UVB irradiation of epidermal keratinocytes results in the activation of the p38 MAPK pathway and subsequently activator protein-1 (AP-1) transcription factor activation and COX-2 expression. AP-1 and COX-2 have been shown to play functional roles in UVB-induced mouse skin carcinogenesis. In this study, the experimental approach was to express a dominant negative p38α MAPK (p38DN) in the epidermis of SKH-1 hairless mice and assess UVB-induced AP-1 activation, COX-2 expression and the skin carcinogenesis response in these mice compared to wild-type littermates. We observed a significant inhibition of UVB-induced AP-1 activation and COX-2 expression in p38DN transgenic mice, leading to a significant reduction of UVB-induced tumor number and growth compared to wild-type littermates in a chronic UVB skin carcinogenesis model. A potential mechanism for this reduction in tumor number and growth rate is an inhibition of chronic epidermal proliferation, observed as reduced Ki-67 staining in p38DN mice compared to wild-type. Although we detected no difference in chronic apoptotic rates between transgenic and non-transgenic mice, analysis of acutely irradiated mice demonstrated that expression of the p38DN transgene significantly inhibited UVB-induced apoptosis of keratinocytes. These results counter the concerns that inhibition of p38 MAPK in a chronic situation could compromise the ability of the skin to eliminate potentially tumorigenic cells. Our data indicate that p38 MAPK is a good target for pharmacological intervention for UV induced skin cancer in patients with sun damaged skin, and suggest that inhibition of p38 signaling reduces skin carcinogenesis by inhibiting COX-2 expression and proliferation of UVB-irradiated cells. PMID:21268131

  19. Antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis in rats.

    PubMed

    Martin, O C B; Lin, C; Naud, N; Tache, S; Raymond-Letron, I; Corpet, D E; Pierre, F H

    2015-01-01

    Epidemiological studies show that heme iron from red meat is associated with increased colorectal cancer risk. In carcinogen-induced-rats, a heme iron-rich diet increases the number of precancerous lesions and raises associated fecal biomarkers. Heme-induced lipoperoxidation measured by fecal thiobarbituric acid reagents (TBARs) could explain the promotion of colon carcinogenesis by heme. Using a factorial design we studied if microbiota could be involved in heme-induced carcinogenesis, by modulating peroxidation. Rats treated or not with an antibiotic cocktail were given a control or a hemoglobin-diet. Fecal bacteria were counted on agar and TBARs concentration assayed in fecal water. The suppression of microbiota by antibiotics was associated with a reduction of crypt height and proliferation and with a cecum enlargement, which are characteristics of germ-free rats. Rats given hemoglobin diets had increased fecal TBARs, which were suppressed by the antibiotic treatment. A duplicate experiment in rats given dietary hemin yielded similar results. These data show that the intestinal microbiota is involved in enhancement of lipoperoxidation by heme iron. We thus suggest that microbiota could play a role in the heme-induced promotion of colorectal carcinogenesis.

  20. Gastric Helicobacter Infection Induces Iron Deficiency in the INS-GAS Mouse

    PubMed Central

    Thomson, Melanie J.; Pritchard, D. Mark; Boxall, Sally A.; Abuderman, Abdul A.; Williams, Jonathan M.; Varro, Andrea; Crabtree, Jean E.

    2012-01-01

    There is increasing evidence from clinical and population studies for a role of H. pylori infection in the aetiology of iron deficiency. Rodent models of Helicobacter infection are helpful for investigating any causal links and mechanisms of iron deficiency in the host. The aim of this study was to investigate the effects of gastric Helicobacter infection on iron deficiency and host iron metabolism/transport gene expression in hypergastrinemic INS-GAS mice. INS-GAS mice were infected with Helicobacter felis for 3, 6 and 9 months. At post mortem, blood was taken for assessment of iron status and gastric mucosa for pathology, immunohistology and analysis of gene expression. Chronic Helicobacter infection of INS- GAS mice resulted in decreased serum iron, transferrin saturation and hypoferritinemia and increased Total iron binding capacity (TIBC). Decreased serum iron concentrations were associated with a concomitant reduction in the number of parietal cells, strengthening the association between hypochlorhydria and gastric Helicobacter-induced iron deficiency. Infection with H. felis for nine months was associated with decreased gastric expression of iron metabolism regulators hepcidin, Bmp4 and Bmp6 but increased expression of Ferroportin 1, the iron efflux protein, iron absorption genes such as Divalent metal transporter 1, Transferrin receptor 1 and also Lcn2 a siderophore-binding protein. The INS-GAS mouse is therefore a useful model for studying Helicobacter-induced iron deficiency. Furthermore, the marked changes in expression of gastric iron transporters following Helicobacter infection may be relevant to the more rapid development of carcinogenesis in the Helicobacter infected INS-GAS model. PMID:23185574

  1. Nebivolol prevents indomethacin-induced gastric ulcer in rats.

    PubMed

    El-Ashmawy, Nahla E; Khedr, Eman G; El-Bahrawy, Hoda A; Selim, Hend M

    2016-07-01

    Gastric ulcer is a very common gastrointestinal disease that may lead to dangerous complications and even death. This study was conducted to evaluate the prophylactic effect of nebivolol against indomethacin [INDO]-induced gastric ulcer. Male Wistar rats were divided into four groups: normal control, ulcer control (INDO only), omeprazole before INDO and nebivolol before INDO. Each rat to receive nebivolol and omeprazole was given the agent orally (by gavage) daily for 10 days prior to induction of ulcer by oral dosing with INDO. Four hours after INDO treatment, all rats were euthanized and their stomachs obtained for measures of gastric acidity, oxidative stress and inflammatory markers, as well as cytoprotective mediators. The results showed that a single oral dose of INDO (100 mg/kg) induced gastric acidity, an ulcer index of 2900 and significantly increased levels of gastric tumor necrosis factor (TNF)-α and malondialdehyde (MDA) and significantly decreased levels of gastric prostaglandin E2 (PGE2), glutathione (GSH) and nitric oxide (NO), compared to in normal control counterpart stomachs. Giving nebivolol before INDO corrected the gastric acidity and resulted in a significant increase in GSH, PGE2 and NO and a significant decrease in TNFα and MDA gastric levels, compared to ulcer control values. Results obtained with nebivolol were comparable to those with omeprazole; the preventive index in the nebivolol group was 90.7% compared to 94.5% in rats in the omeprazole group. These studies showed that nebivolol provided a valuable role in preventing gastric ulcers induced by INDO and provided a promise for potentially protecting hypertensive patients from experiencing gastric ulcer. Thus, it is possible that, pending further studies, nebivolol could be used for pre-exposure prophylaxis from gastric ulcer in these patients.

  2. Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility

    PubMed Central

    Takeuchi, Koji

    2012-01-01

    This article reviews the pathogenic mechanism of non-steroidal anti-inflammatory drug (NSAID)-induced gastric damage, focusing on the relation between cyclooxygenase (COX) inhibition and various functional events. NSAIDs, such as indomethacin, at a dose that inhibits prostaglandin (PG) production, enhance gastric motility, resulting in an increase in mucosal permeability, neutrophil infiltration and oxyradical production, and eventually producing gastric lesions. These lesions are prevented by pretreatment with PGE2 and antisecretory drugs, and also via an atropine-sensitive mechanism, not related to antisecretory action. Although neither rofecoxib (a selective COX-2 inhibitor) nor SC-560 (a selective COX-1 inhibitor) alone damages the stomach, the combined administration of these drugs provokes gastric lesions. SC-560, but not rofecoxib, decreases prostaglandin E2 (PGE2) production and causes gastric hypermotility and an increase in mucosal permeability. COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib. The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility. In addition, selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions, including adrenalectomy, arthritis, and Helicobacter pylori-infection. In summary, gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage, and the response, causally related with PG deficiency due to COX-1 inhibition, occurs prior to other pathogenic events such as increased mucosal permeability; and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility, and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition. PMID:22611307

  3. Caffeic acid directly targets ERK1/2 to attenuate solar UV-induced skin carcinogenesis

    PubMed Central

    Yang, Ge; Fu, Yang; Malakhova, Margarita; Kurinov, Igor; Zhu, Feng; Yao, Ke; Li, Haitao; Chen, Hanyong; Li, Wei; Lim, Do Young; Sheng, Yuqiao; Bode, Ann M.; Dong, Ziming; Dong, Zigang

    2014-01-01

    Caffeic acid (3,4-dihydroxycinnamic acid) is a well-known phenolic phytochemical present in coffee and reportedly has anticancer activities. However, the underlying molecular mechanisms and targeted proteins involved in the suppression of carcinogenesis by caffeic acid are not fully understood. In this study, we report that caffeic acid significantly inhibits colony formation of human skin cancer cells and EGF-induced neoplastic transformation of HaCaT cells dose-dependently. Caffeic acid topically applied to dorsal mouse skin significantly suppressed tumor incidence and volume in a solar UV-induced skin carcinogenesis mouse model. A substantial reduction of phosphorylation in mitogen-activated protein kinase signaling was observed in mice treated with caffeic acid either before or after solar UV exposure. Caffeic acid directly interacted with ERK1/2 and inhibited ERK1/2 activities in vitro. Importantly, we resolved the co-crystal structure of ERK2 complexed with caffeic acid. Caffeic acid interacted directly with ERK2 at amino acid residues Q105, D106 and M108. Moreover, A431 cells expressing knockdown of ERK2 lost sensitivity to caffeic acid in a skin cancer xenograft mouse model. Taken together, our results suggest that caffeic acid exerts chemopreventive activity against solar UV-induced skin carcinogenesis by targeting ERK1 and 2. PMID:25104643

  4. Suppressive function of RKTG on chemical carcinogen-induced skin carcinogenesis in mouse.

    PubMed

    Xie, Xiaoduo; Zhang, Yixuan; Jiang, Yuhui; Liu, Weizhong; Ma, Hong; Wang, Zhenzhen; Chen, Yan

    2008-08-01

    Raf kinase trapping to Golgi (RKTG) is a newly characterized negative regulator of the Ras-Raf-MEK-ERK signaling pathway via sequestrating Raf-1 to the Golgi apparatus. However, little is known about the physiological functions of RKTG in mitogenic pathway and carcinogenesis. Here, we describe a suppressive role of RKTG in skin carcinogenesis by analyzing chemical carcinogen-induced tumorigenesis. Epidermis hyperplasia and proliferation are increased in RKTG-deficient mice (RKTG(-/-)) after acute treatment with 7, 12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). Using a two-stage DMBA/TPA carcinogenesis protocol on mouse skin, the number and size of papillomas are increased in RKTG(-/-) mice, accompanied by shortened tumor latency and enhanced keratinocyte proliferation. The regression of the carcinogen-induced tumors is also prolonged in RKTG(-/-) mice. Consistently, the levels of Raf-1 and extracellular signal-regulated kinase phosphorylation in primary keratinocytes as well as skin tumors are elevated when RKTG is disrupted. Collectively, our results indicate that RKTG has a suppressive activity in chemical carcinogen-induced mitogenesis and tumor formation in mouse skin.

  5. Effects of immunostimulation with OK432, coenzyme Q10, or levamisole on dimethylhydrazine-induced colonic carcinogenesis in rats.

    PubMed

    Suzuki, H; Yamamoto, J; Iwata, Y; Matsumoto, K; Iriyama, K

    1986-03-01

    Effects of immunostimulation with OK432, Coenzyme Q10 (Co-Q10), or levamisole on dimethylhydrazine (DMH)-induced colonic carcinogenesis were investigated in 45 Donryu-rats. The manipulation with one of these immunopotentiators did not prevent DMH-induced colonic carcinogenesis in these rats. However, the number of tumors was significantly reduced and the incidence of invasive carcinomas decreased by immunostimulation. The treatment also reduced the number of lesions with epithelial dysplasia within the flat colonic mucosa.

  6. Radiation-induced instability and its relation to radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Ullrich, R. L.; Ponnaiya, B.

    1998-01-01

    PURPOSE: A model that identifies radiation-induced genetic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer was previously proposed. In this paper ongoing experiments are discussed which are designed to test this model and its predictions in mouse mammary epithelial cells. RESULTS: Several lines of evidence are presented that appear to support this model: first, the development of delayed mutations in p53 following irradiation in altered growth variants; secondly, the high frequencies for the induction of both instability and transformation following irradiation in mammary epithelial cells; and finally, the demonstration that susceptibility to the induction of cytogenetic instability is a heritable trait that correlates with susceptibility to transformation and radiation-induced mammary cancer. Mice resistant to transformation and mammary cancer development are also resistant to the development of instability after irradiation. In contrast, mice sensitive to transformation and cancer are also sensitive to the development of cytogenetic instability. CONCLUSIONS: Data from this laboratory and from the studies cited above suggest a specific, and perhaps unique, role for radiation-induced instability as a critical early event associated with initiation of the carcinogenic process.

  7. Radiation-induced instability and its relation to radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Ullrich, R. L.; Ponnaiya, B.

    1998-01-01

    PURPOSE: A model that identifies radiation-induced genetic instability as the earliest cellular event in the multi-step sequence leading to radiation-induced cancer was previously proposed. In this paper ongoing experiments are discussed which are designed to test this model and its predictions in mouse mammary epithelial cells. RESULTS: Several lines of evidence are presented that appear to support this model: first, the development of delayed mutations in p53 following irradiation in altered growth variants; secondly, the high frequencies for the induction of both instability and transformation following irradiation in mammary epithelial cells; and finally, the demonstration that susceptibility to the induction of cytogenetic instability is a heritable trait that correlates with susceptibility to transformation and radiation-induced mammary cancer. Mice resistant to transformation and mammary cancer development are also resistant to the development of instability after irradiation. In contrast, mice sensitive to transformation and cancer are also sensitive to the development of cytogenetic instability. CONCLUSIONS: Data from this laboratory and from the studies cited above suggest a specific, and perhaps unique, role for radiation-induced instability as a critical early event associated with initiation of the carcinogenic process.

  8. Effect of sodium meclofenamate on ultraviolet radiation induced carcinogenesis

    SciTech Connect

    Ambrus, J.L.; Ambrus, C.M.; Pickren, J.W.; Klein, E.

    1984-01-01

    Sodium meclofenamate (Meclomen), an antiprostaglandin antileukotriene agent, was found in previous studies to protect primates against x-ray induced brain edema, esophagitis and cystitis. In the present study, it appeared to protect hairless mice against the carcinogenic effect of ultraviolet B-radiation.

  9. Neglected role of hookah and opium in gastric carcinogenesis: a cohort study on risk factors and attributable fractions.

    PubMed

    Sadjadi, Alireza; Derakhshan, Mohammad H; Yazdanbod, Abbas; Boreiri, Majid; Parsaeian, Mahbubeh; Babaei, Masoud; Alimohammadian, Masoomeh; Samadi, Fatemeh; Etemadi, Arash; Pourfarzi, Farhad; Ahmadi, Emad; Delavari, Alireza; Islami, Farhad; Farzadfar, Farshad; Sotoudeh, Masoud; Nikmanesh, Arash; Alizadeh, Behrooz Z; de Bock, Geertruida H; Malekzadeh, Reza

    2014-01-01

    A recent study showed an association between hookah/opium use and gastric cancer but no study has investigated the relationship with gastric precancerous lesions. We examined the association between hookah/opium and gastric precancerous lesions and subsequent gastric cancer. In a population-based cohort study, 928 randomly selected, healthy, Helicobacter pylori-infected subjects in Ardabil Province, Iran, were followed for 10 years. The association between baseline precancerous lesions and lifestyle risk factors (including hookah/opium) was analyzed using logistic regression and presented as odds ratios (ORs) and 95% confidence intervals (CIs). We also calculated hazard ratios (HRs) and 95% CIs for the associations of lifestyle risk factors and endoscopic and histological parameters with incident gastric cancers using Cox regression models. Additionally, the proportion of cancers attributable to modifiable risk factors was calculated. During 9,096 person-years of follow-up, 36 new cases of gastric cancer were observed (incidence rate: 3.96/1,000 persons-years). Opium consumption was strongly associated with baseline antral (OR: 3.2; 95% CI: 1.2-9.1) and body intestinal metaplasia (OR: 7.3; 95% CI: 2.5-21.5). Opium (HR: 3.2; 95% CI: 1.4-7.7), hookah (HR: 3.4; 95% CI: 1.7-7.1) and cigarette use (HR: 3.2; 95% CI: 1.4-7.5), as well as high salt intake, family history of gastric cancer, gastric ulcer and histological atrophic gastritis and intestinal metaplasia of body were associated with higher risk of gastric cancer. The fraction of cancers attributable jointly to high salt, low fruit intake, smoking (including hookah) and opium was 93% (95% CI: 83-98). Hookah and opium use are risk factors for gastric cancer as well as for precancerous lesions. Hookah, opium, cigarette and high salt intake are important modifiable risk factors in this high-incidence gastric cancer area.

  10. Bamboo Salt Suppresses Colon Carcinogenesis in C57BL/6 Mice with Chemically Induced Colitis.

    PubMed

    Ju, Jaehyun; Lee, Ga-Young; Kim, Yoon-Se; Chang, Hee Kyung; Do, Myoung-Sool; Park, Kun-Young

    2016-11-01

    The aim of our experiment was to evaluate the anticancer effect of bamboo salt (BS) on C57BL/6 mice in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer model. BS, solar salt, and purified salt were evaluated for their protective effects during AOM/DSS-induced colon carcinogenesis in C57BL/6 mice. BS, especially after baking for nine separate intervals (BS9x), suppressed colon carcinogenesis in the mice. BS9x decreased colon length shortening, weight-to-length ratios, and tumor counts. Pathological evidence from histological evaluation by hematoxylin and eosin staining also revealed suppression of tumorigenesis. BS9x lowered serum levels of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) to close to those of the Normal group. Additionally, BS9x suppressed colon mRNA expression of proinflammatory factors and significantly regulated mRNA levels of the apoptosis-related factors, Bax and Bcl-2, and the cell cycle-related genes, p21 and p53. Additionally, immunohistochemistry showed that BS promoted p21 expression in the colon. Taken together, the results indicate that BS exhibited anticancer efficacy by modulating apoptosis- and inflammation-related gene expression during colon carcinogenesis in mice, and repetition in baking cycles of BS enhanced its anticancer functionality.

  11. Suppression of osteopontin inhibits chemically induced hepatic carcinogenesis by induction of apoptosis in mice

    PubMed Central

    Lee, Su-Hyung; Park, Jun-Won; Woo, Sang-Ho; Go, Du-Min; Kwon, Hyo-Jung; Jang, Ja-June; Kim, Dae-Yong

    2016-01-01

    Previous clinical reports have found elevated osteopontin (OPN) levels in tumor tissues to be indicative of greater malignancy in human hepatocellular carcinoma (HCC). However, the role of OPN on carcinogenesis and its underlying mechanism remain unclear. In the present study, we investigated the oncogenic role of OPN in diethylnitrosamine (DEN)-induced hepatic carcinogenesis in mice. The overall incidence of hepatic tumors at 36 weeks was significantly lower in OPN knockout (KO) mice than in wild-type (WT) mice. Apoptosis was significantly enhanced in OPN KO mice, and was accompanied by the downregulation of epidermal growth factor receptor (EGFR). In the in vitro study, OPN suppression also led to lower mRNA and protein levels of EGFR associated with the downregulation of c-Jun in Hep3B and Huh7 human HCC cells lines, which resulted in increased apoptotic cell death in both cell lines. Moreover, a positive correlation was clearly identified between the expression of OPN and EGFR in human HCC tissues. These data demonstrate that the OPN deficiency reduced the incidence of chemically induced HCC by suppressing EGFR-mediated anti-apoptotic signaling. An important implication of our findings is that OPN positively contributes to hepatic carcinogenesis. PMID:27888617

  12. Sequential gene promoter methylation during HPV-induced cervical carcinogenesis.

    PubMed

    Henken, F E; Wilting, S M; Overmeer, R M; van Rietschoten, J G I; Nygren, A O H; Errami, A; Schouten, J P; Meijer, C J L M; Snijders, P J F; Steenbergen, R D M

    2007-11-19

    We aimed to link DNA methylation events occurring in cervical carcinomas to distinct stages of HPV-induced transformation. Methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) analysis of cervical carcinomas revealed promoter methylation of 12 out of 29 tumour suppressor genes analysed, with MGMT being most frequently methylated (92%). Subsequently, consecutive stages of HPV16/18-transfected keratinocytes (n=11), ranging from pre-immortal to anchorage-independent phenotypes, were analysed by MS-MLPA. Whereas no methylation was evident in pre-immortal cells, progression to anchorage independence was associated with an accumulation of frequent methylation events involving five genes, all of which were also methylated in cervical carcinomas. TP73 and ESR1 methylation became manifest in early immortal cells followed by RARbeta and DAPK1 methylation in late immortal passages. Complementary methylation of MGMT was related to anchorage independence. Analysis of nine cervical cancer cell lines, representing the tumorigenic phenotype, revealed in addition to these five genes frequent methylation of CADM1, CDH13 and CHFR. In conclusion, eight recurrent methylation events in cervical carcinomas could be assigned to different stages of HPV-induced transformation. Hence, our in vitro model system provides a valuable tool to further functionally address the epigenetic alterations that are common in cervical carcinomas.

  13. Sequential gene promoter methylation during HPV-induced cervical carcinogenesis

    PubMed Central

    Henken, F E; Wilting, S M; Overmeer, R M; van Rietschoten, J G I; Nygren, A O H; Errami, A; Schouten, J P; Meijer, C J L M; Snijders, P J F; Steenbergen, R D M

    2007-01-01

    We aimed to link DNA methylation events occurring in cervical carcinomas to distinct stages of HPV-induced transformation. Methylation specific-multiplex ligation-dependent probe amplification (MS-MLPA) analysis of cervical carcinomas revealed promoter methylation of 12 out of 29 tumour suppressor genes analysed, with MGMT being most frequently methylated (92%). Subsequently, consecutive stages of HPV16/18-transfected keratinocytes (n=11), ranging from pre-immortal to anchorage-independent phenotypes, were analysed by MS-MLPA. Whereas no methylation was evident in pre-immortal cells, progression to anchorage independence was associated with an accumulation of frequent methylation events involving five genes, all of which were also methylated in cervical carcinomas. TP73 and ESR1 methylation became manifest in early immortal cells followed by RARβ and DAPK1 methylation in late immortal passages. Complementary methylation of MGMT was related to anchorage independence. Analysis of nine cervical cancer cell lines, representing the tumorigenic phenotype, revealed in addition to these five genes frequent methylation of CADM1, CDH13 and CHFR. In conclusion, eight recurrent methylation events in cervical carcinomas could be assigned to different stages of HPV-induced transformation. Hence, our in vitro model system provides a valuable tool to further functionally address the epigenetic alterations that are common in cervical carcinomas. PMID:17971771

  14. Prevention by alpha-difluoromethylornithine of skin carcinogenesis and immunosuppression induced by ultraviolet irradiation.

    PubMed

    Gensler, H L

    1991-01-01

    Administration of alpha-difluoromethylornithine (DFMO) to mice was found to inhibit both the cutaneous carcinogenesis and the immunosuppression induced by ultraviolet B (UVB) irradiation. BALB/cAnNTacfBR mice were given 1% F2MeOrn in their drinking water throughout the experiment. After 3 weeks, mice received UVB irradiation consisting of five 30-min exposures per week to banks of six FS40 Westinghouse sunlamps. In the photocarcinogenesis study, mice received a total dose of approximately 1273 kJ m-2. Skin cancer incidence in UV-irradiated mice was 38% 28 weeks after the first UV exposure; DFMO reduced this incidence to 9% (P = 0.025, log-rank test). Although DFMO has been demonstrated to be chemopreventive of chemical carcinogenesis, this is the first report that it is effective against cancers induced by a physical carcinogen. The immunosuppression induced by UVB irradiation prevents the host from rejecting antigenic, syngeneic UV-induced tumors, which normal mice can reject. The level of immunosuppression in UV-irradiated mice treated with DFMO was measured by a passive-transfer assay. Splenocytes from UV-irradiated mice to naive mice prevented the recipients from rejecting 20/24 UV-induced tumor challenges, whereas splenocytes from UV-irradiated mice treated with DFMO did not prevent recipients from rejecting such challenges (2/24 grew). The difference between these values was significant (P less than 0.001, two-sample test for binomial proportions). Phenotypic analysis of splenocytes used in the passive transfer, using a biotin-avidin-immunoperoxidase technique, revealed that DFMO treatment prevented the reduction of Ia expression normally seen in UV-irradiated mice. Thus, administration of DFMO reduced skin carcinogenesis and immunosuppression induced by UVB irradiation.

  15. Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats

    PubMed Central

    Al-Rejaie, Salim S; Aleisa, Abdulaziz M; Al-Yahya, Abdulaziz A; Bakheet, Saleh A; Alsheikh, Abdulmalik; Fatani, Amal G; Al-Shabanah, Othman A; Sayed-Ahmed, Mohamed M

    2009-01-01

    AIM: To investigate whether carnitine deficiency is a risk factor during the development of diethylnitrosamine (DENA)-induced hepatic carcinogenesis. METHODS: A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group. Rats in group 1 (control group) received a single intraperitoneal (i.p.) injection of normal saline. Animals in group 2 (carnitine-supplemented group) were given L-carnitine (200 mg/kg per day) in drinking water for 8 wk. Animals in group 3 (carnitine-depleted group) were given D-carnitine (200 mg/kg per day) and mildronate (200 mg/kg per day) in drinking water for 8 wk. Rats in group 4 (DENA group) were injected with a single dose of DENA (200 mg/kg, i.p.) and 2 wk later received a single dose of carbon tetrachloride (2 mL/kg) by gavage as 1:1 dilution in corn oil. Animals in group 5 (DENA-carnitine depleted group) received the same treatment as group 3 and group 4. Rats in group 6 (DENA-carnitine supplemented group) received the same treatment as group 2 and group 4. RESULTS: Administration of DENA resulted in a significant increase in alanine transaminase (ALT), gamma-glutamyl transferase (G-GT), alkaline phosphatase (ALP), total bilirubin, thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NOx) and a significant decrease in reduced glutathione (GSH), glutathione peroxidase (GSHPx), catalase (CAT) and total carnitine content in liver tissues. In the carnitine-depleted rat model, DENA induced a dramatic increase in serum ALT, G-GT, ALP and total bilirubin, as well as a progressive reduction in total carnitine content in liver tissues. Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes, TBARS and NOx, and a decrease in total carnitine, GSH, GSHPx, and CAT induced by DENA, compared with the control values. Histopathological examination of liver tissues confirmed the biochemical data, where L-carnitine prevented DENA-induced hepatic

  16. Duodenogastric reflux and foregut carcinogenesis.

    PubMed

    Miwa, K; Hattori, T; Miyazaki, I

    1995-03-15

    Epidemiologic cohort studies have established that after distal gastric resection, there is a higher risk of gastric carcinoma. It is likely that a main factor of this higher risk is the excessive duodenogastric reflux induced by surgery, because the incidence of stump carcinomas is higher in Billroth II than in Billroth I, and most of the stump carcinomas are located near the stoma. In addition, several groups of investigators have suggested that duodenogastric reflux per se induces stump carcinomas in rats. There is another human duodenogastric reflux, the primary duodenogastric reflux, through the pylorus. Experiments in animals have demonstrated that this type of duodenal reflux also induces gastric carcinomas in the antrum of the stomach that has not undergone surgery. Recent clinical attention has focused on the role of duodenogastric reflux in the pathogenesis of Barrett's esophagus and subsequent esophageal adenocarcinomas. Experimentally, reflux of duodenal contents into the esophagus can cause not only Barrett's esophagus and subsequent adenocarcinomas, but also squamous cell carcinomas. These findings suggest that duodenogastric reflux may be implicated in gastric and esophageal, that is, foregut carcinogenesis.

  17. Tungsten-induced carcinogenesis in human bronchial epithelial cells

    PubMed Central

    Laulicht, Freda; Brocato, Jason; Cartularo, Laura; Vaughan, Joshua; Wu, Feng; Kluz, Thomas; Sun, Hong; Oksuz, Betul Akgol; Shen, Steven; Paena, Massimilano; Medici, Serenella; Zoroddu, Maria Antonietta; Costa, Max

    2015-01-01

    Metals such as arsenic, cadmium, beryllium, and nickel are known human carcinogens; however, other transition metals, such as tungsten (W), remain relatively uninvestigated with regard to their potential carcinogenic activity. Tungsten production for industrial and military applications has almost doubled over the past decade and continues to increase. Here, for the first time, we demonstrate tungsten’s ability to induce carcinogenic related endpoints including cell transformation, increased migration, xenograft growth in nude mice, and the activation of multiple cancer related pathways in transformed clones as determined by RNA seq. Human bronchial epithelial cell line (Beas-2B) exposed to tungsten developed carcinogenic properties. In a soft agar assay, tungsten-treated cells formed more colonies than controls and the tungsten-transformed clones formed tumors in nude mice. RNA-sequencing data revealed that the tungsten-transformed clones altered the expression of many cancer-associated genes when compared to control clones. Genes involved in lung cancer, leukemia, and general cancer genes were deregulated by tungsten. Taken together, our data shows the carcinogenic potential of tungsten. Further tests are needed, including in vivo and human studies, in order to validate tungsten as a carcinogen to humans. PMID:26164860

  18. Quercetin Reverses Rat Liver Preneoplastic Lesions Induced by Chemical Carcinogenesis.

    PubMed

    Carrasco-Torres, Gabriela; Monroy-Ramírez, Hugo Christian; Martínez-Guerra, Arturo Axayacatl; Baltiérrez-Hoyos, Rafael; Romero-Tlalolini, María de Los Ángeles; Villa-Treviño, Saúl; Sánchez-Chino, Xariss; Vásquez-Garzón, Verónica Rocío

    2017-01-01

    Quercetin is a flavonoid widely studied as a chemopreventive agent in different types of cancer. Previously, we reported that quercetin has a chemopreventive effect on the liver-induced preneoplastic lesions in rats. Here, we evaluated if quercetin was able not only to prevent but also to reverse rat liver preneoplastic lesions. We used the modified resistant hepatocyte model (MRHM) to evaluate this possibility. Treatment with quercetin was used 15 days after the induction of preneoplastic lesions. We found that quercetin reverses the number of preneoplastic lesions and their areas. Our results showed that quercetin downregulates the expression of EGFR and modulates this signaling pathway in spite of the activated status of EGFR as detected by the upregulation of this receptor, with respect to that observed in control rats. Besides, quercetin affects the phosphorylation status of Src-1, STAT5, and Sp-1. The better status of the liver after the treatment with quercetin could also be confirmed by the recovery in the expression of IGF-1. In conclusion, we suggest that quercetin reversed preneoplastic lesions by EGFR modulation and the activation state of Src, STAT5, and Sp1, so as the basal IGF-1.

  19. 65Zn kinetics as a biomarker of DMH induced colon carcinogenesis.

    PubMed

    Chadha, Vijayta Dani; Dhawan, Davinder

    2010-01-01

    Dietary factors are considered crucial for the prevention of initiating events in the multistep progression of colon carcinoma. There is substantial evidence that zinc may play a pivotal role in host defense against several malignancies, including colon cancer. The present study was conducted to evaluate the kinetics of (65)Zn utilization following experimental colon carcinogenesis in rat model. Twenty rats were segregated into two groups viz., untreated control and dimethylhydrazine (DMH) treated. Colon carcinogenesis was established through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 16 weeks. Whole body (65)Zn kinetics followed two compartment kinetics, with Tb(1) representing the initial fast component of the biological half-life and Tb(2), the slower component. The present study revealed a significant depression in the Tb(1) and Tb(2) components of (65)Zn in DMH treated rats. Further, DMH treatment caused a significant increase in the percent uptake values of (65)Zn in the colon, small intestine, kidney and blood, whereas a significant decrease was observed in the liver. Subcellular distribution revealed a significant increase in (65)Zn uptake in the mitochondrial and microsomal fractions following 16 weeks of DMH supplementation. In conclusion, the present study demonstrated a slow mobilization of (65)Zn during promotion of experimentally induced colon carcinogenesis and provides a physiological basis for the role of (65)Zn in colon tumorigenesis, which may have clinical implications in the management of colon cancer.

  20. Inhibition of azoxymethane-induced rat colon carcinogenesis by potassium hydrogen D-glucarate.

    PubMed

    Yoshimi, N; Walaszek, Z; Mori, H; Hanausek, M; Szemraj, J; Slaga, T J

    2000-01-01

    While calcium D-glucarate was shown to inhibit chemical carcinogenesis in various animal models, the effect of potassium hydrogen D-glucarate has not been extensively investigated. In the present study, potassium hydrogen D-glucarate markedly inhibited azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. Potassium hydrogen D-glucarate (PHG) or potassium hydrogen carbonate (PHC) were administered to rats in a diet (140 mmol/kg). Continual post-initiation treatment with potassium hydrogen D-glucarate reduced both tumor incidence and multiplicity at sacrifice by ca. 60%, while PHC had no effect. amelioration of overexpression of the betaG gene in rat colon carcinomas was observed using RT-PCR and Northern blot analysis. We hypothesize that previously demonstrated conversion of PHG to D-glucaro-1,4-lactone, a potent inhibitor of beta-glucuronidase (betaG), may be responsible for this effect. The mechanism of PHG inhibition of colon carcinogenesis may also involve suppression of cell proliferation and possibly alterations in cholesterol synthesis or cholesterol metabolism to bile acids. In conclusion, PHG possesses excellent potential as a natural, apparently non-toxic inhibitor to prevent colon cancer.

  1. Roles of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 expression and beta-catenin activation in gastric carcinogenesis in N-methyl-N-nitrosourea-treated K19-C2mE transgenic mice.

    PubMed

    Takasu, Shinji; Tsukamoto, Tetsuya; Cao, Xue-Yuan; Toyoda, Takeshi; Hirata, Akihiro; Ban, Hisayo; Yamamoto, Masami; Sakai, Hiroki; Yanai, Tokuma; Masegi, Toshiaki; Oshima, Masanobu; Tatematsu, Masae

    2008-12-01

    K19-C2mE transgenic (Tg) mice, simultaneously expressing cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) in the gastric mucosa under the cytokeratin 19 gene promoter, were here treated with N-methyl-N-nitrosourea (MNU) and inoculated with Helicobacter pylori (H. pylori) to investigate gastric carcinogenesis. Wild-type (WT) and Tg mice undergoing MNU treatment frequently developed tumors in the pyloric region (100% and 94.7%, respectively); multiplicity in Tg was higher than that in WT (P < 0.05) with H. pylori infection. Larger pyloric tumors were more frequently observed in Tg than in WT (P < 0.05). In addition, Tg developed fundic tumors, where WT did not. No gastric tumors were observed without MNU treatment. Transcripts of TNF-alpha, iNOS, IL-1beta, and CXCL14 were up-regulated with H. pylori infection in both genotypes and were also increased more in Tg than in WT within H. pylori-inoculated animals. Immunohistochemical analysis demonstrated significantly greater beta-catenin accumulation in pyloric tumors, compared with those in the fundus (P < 0.01) with mutations of exon 3; 18.2% and 31.6% in MNU-alone and MNU + H. pylori-treated WT, whereas 21.4% and 62.5% was observed in the Tg, respectively; the latter significantly higher (P < 0.05), suggesting the role of H. pylori in Wnt activation. In conclusion, K19-C2mE mice promoted gastric cancer in both fundic and pyloric regions. Furthermore beta-catenin activation may play the important role of pyloric carcinogenesis especially in H. pylori-infected Tg. Induction of various inflammatory cytokines in addition to overexpression of COX-2/mPGES-1 could be risk factors of gastric carcinogenesis and may serve as a better gastric carcinogenesis model.

  2. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    SciTech Connect

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-06-27

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C {r_arrow} A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C {r_arrow} T, two C {r_arrow} A, one C {r_arrow} G, and one A {r_arrow} T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab.

  3. [Biological effects of arsenic and diseases: The mechanisms involved in arsenic-induced carcinogenesis].

    PubMed

    Suzuki, Takehiro; Takumi, Shota; Okamura, Kazuyuki; Nohara, Keiko

    2016-07-01

    Chronic arsenic exposure is associated with many diseases, including cancers. Our study using in vivo assay in gpt-delta transgenic mice showed that arsenic particularly induces G : C to T : A transversions, a mutation type induced through oxidative-stress-induced 8-OHdG formation. Gestational arsenic exposure of C3H mice was reported to increase hepatic tumor incidence. We showed that gestational arsenic exposure increased hepatic tumors having activated oncogene Ha-ras by C to A mutation. We also showed that DNA methylation status of Fosb region is implicated in tumor augmentation by gestational arsenic exposure. We further showed that long-term arsenic exposure induces premature senescence. Recent studies reported that senescence is involved in not only tumor suppression, but also tumorgenesis. All these effects of arsenic might be involved in arsenic-induced carcinogenesis.

  4. Role of mitochondria, ROS, and DNA damage in arsenic induced carcinogenesis.

    PubMed

    Lee, Chih-Hung; Yu, Hsin-Su

    2016-06-01

    The International Agency for Research on Cancer (IARC) declared arsenic a class I carcinogen. Arsenic exposure induces several forms of human cancers, including cancers of skin, lung, liver, and urinary bladder. The majority of the arsenic-induced cancers occur in skin. Among these, the most common is Bowen's disease, characterized by epidermal hyperplasia, full layer epidermal dysplasia, leading to intraepidermal carcinoma as well as apoptosis, and moderate dermal infiltrates, which require the participation of mitochondria. The exact mechanism underlying arsenic induced carcinogenesis remains unclear, although increased reactive oxidative stresses, leading to chromosome abnormalities and uncontrolled growth, and aberrant immune regulations might be involved. Here, we highlight how increased mitochondrial biogenesis and oxidative stress lead to mitochondrial DNA damage and mutation in arsenic induced cancers. We also provide therapeutic rationale for targeting mitochondria in the treatment of arsenic induced cancers.

  5. Adrenalectomy abolishes hypergravity-induced gastric acid hyposecretion

    PubMed Central

    Na, Kiyong; Kim, Hyun-Soo

    2017-01-01

    Jet fighter pilots experience high gravitational acceleration forces in the cephalocaudal direction (+Gz), causing severe stress. Stress affects different physiological functions of the gastrointestinal tract. Although the effects of exposure to hypergravity on cardiovascular and cerebral functions have been the subject of numerous studies, crucial information regarding potential pathophysiological alterations following hypergravity exposure in the gastrointestinal tract is lacking. We recently documented a significant decrease in gastric secretory activity in rats after acute exposure to hypergravity. In the present study, we investigated the effects of adrenalectomy on gastric acid secretion and plasma gastrin level in hypergravity-exposed rats. Male Sprague-Dawley rats were adrenalectomized and exposed to +10Gz three times for 3 min. Gastric juice and blood samples were collected, and the volume and total acidity of gastric juice and plasma level of gastrin were measured. Consistent with our previous data, acute exposure to +10Gz significantly altered the gastric juice parameters in the sham-operated rats. The volume (P < 0.001) and acidity (P < 0.001) of gastric juice in the hypergravity-exposed rats were significantly lower than those in the nonexposed rats. In contrast, in adrenalectomized rats, the differences in the gastric juice volume (P = 0.712) and acidity (P = 0.279) were not statistically significant between the hypergravity-exposed and nonexposed rats. We demonstrated that adrenalectomy abolished hypergravity-induced gastric acid hyposecretion, but did not influence gastrin release. These findings suggest that the adrenal glands are required for hypergravity-induced gastric acid hyposecretion. PMID:28430608

  6. Antioxidant butylated hydroxyanisole inhibits estrogen-induced breast carcinogenesis in female ACI rats.

    PubMed

    Singh, Bhupendra; Mense, Sarah M; Remotti, Fabrizio; Liu, Xinhua; Bhat, Hari K

    2009-01-01

    Exposure to estrogens is suggested to be a risk factor in human breast cancer development. The mechanisms underlying estrogen-induced cancer have not been fully elucidated. Both estrogen receptor (ER)-mediated proliferative processes and ER-independent generation of oxidative stress are suggested to play important roles in estrogen-induced breast carcinogenesis. In the current study, we investigated the role of oxidative stress in breast carcinogenesis using the ACI rat model of mammary tumorigenesis. Female ACI rats were treated with 17beta-estradiol (E(2)), butylated hydroxyanisole (BHA), or a combination of E(2) + BHA for up to 240 days. Cotreatment of rats with E(2) + BHA reduced estrogen-induced breast tumor development with tumor incidence of 24%, a significant decrease relative to E(2) where tumor incidence was 82%. Proliferative changes in the breast tissue of E(2) + BHA-treated animals were similar to those observed in E(2)-treated animals. Tissue levels of 8-isoprostane, a marker of oxidant stress, as well as the activities of antioxidant enzymes including glutathione peroxidase, superoxide dismutase, and catalase were quantified in the breast tissues of rats treated with E(2) + BHA and compared to activity levels found in E(2)-treated animals and respective age-matched controls. Cotreatment with BHA inhibited E(2)-mediated increases in 8-isoprostane levels as well as activities of antioxidant enzymes. In summary, these data suggest that estrogen-mediated oxidant stress plays a critical role in the development of estrogen-dependent breast cancers and BHA inhibits E(2)-dependent breast carcinogenesis by decreasing oxidant stress.

  7. Protective Effect of Lactobacillus casei on DMH-Induced Colon Carcinogenesis in Mice.

    PubMed

    Irecta-Nájera, Cesar Antonio; Del Rosario Huizar-López, María; Casas-Solís, Josefina; Castro-Félix, Patricia; Santerre, Anne

    2017-03-18

    The administration of probiotics is a promising approach to reduce the prevalence of colon cancer, a multifactorial disease, with hereditary factors, as well as environmental lifestyle-related risk factors. Biogenic polyamines, putrescine, spermidine, and spermine are small cationic molecules with great roles in cell proliferation and differentiation as well as regulation of gene expression. Ornithine decarboxylase is the first rate-limiting enzyme for polyamine synthesis, and upregulation of ornithine decarboxylase activity and polyamine metabolism has been associated with abnormal cell proliferation. This paper is focused on studying the protective role of Lactobacillus casei ATCC 393 in a chemically induced mouse model of colon carcinogenesis, directing our attention on aberrant crypt foci as preneoplastic markers, and on polyamine metabolism as a possible key player in carcinogenesis. BALB/c mice were administered 1,2-dimethylhydrazine dihydrochloride (DMH) to induce colon cancer (20 mg/kg body weight, subcutaneous, twice a week for 24 weeks). L. casei ATCC 393 was given orally (10(6) CFU, twice a week), 2 weeks before DMH administration. Hematoxylin and eosin staining, high-performance liquid chromatography, and Western blotting were used to evaluate aberrant crypt foci, urinary polyamines, and ornithine decarboxylase expression in the colon. The experimental data showed that the preventive administration of L. casei ATCC 393 may delay the onset of cancer as it significantly reduced the number of DMH-induced aberrant crypt foci, the levels of putrescine, and the expression of ornithine decarboxylase. Hence, this probiotic strain has a prospective role in protection against colon carcinogenesis, and its antimutagenic activity may be associated with the maintenance of polyamine metabolism.

  8. Localization of gastric peroxidase and its inhibition by mercaptomethylimidazole, an inducer of gastric acid secretion.

    PubMed Central

    Bandyopadhyay, U; Bhattacharyya, D K; Chatterjee, R; Banerjee, R K

    1992-01-01

    Mercaptomethylimidazole (MMI) is a potent inducer of gastric acid secretion which is associated with significant inhibition of peroxidase activity of rat gastric mucosa in vivo. A time-dependent increase in acid secretion correlates well with time-dependent decrease in the peroxidase activity. In a chamber experiment in vitro using isolated gastric mucosa, MMI stimulates acid secretion, showing an almost linear response up to 600 microM. The time-dependent increase in acid secretion is also correlated with time-dependent inhibition of the peroxidase activity. This effect is not mediated through oxidation of MMI by flavin-containing mono-oxygenase, which is absent from gastric mucosa. The peroxidase has been localized mainly in parietal cells isolated and purified from gastric mucosa by controlled digestion with collagenase followed by Percoll-density-gradient centrifugation. Peroxidase activity was further localized in the outer membrane of the purified mitochondria of the parietal cell by some membrane-impermeant reagents, indicating outward orientation of the enzyme. MMI can inhibit the peroxidase activity of both the parietal cell and its mitochondria in a concentration-dependent manner. The possible involvement of the parietal-cell peroxidase-H2O2 system in MMI-induced acid secretion may be suggested. PMID:1318028

  9. Human papillomavirus-induced carcinogenesis and the ubiquitin-proteasome system.

    PubMed

    Scheffner, Martin; Whitaker, Noel J

    2003-02-01

    Certain types of human papillomaviruses have been etiologically associated with malignant lesions, most notably with cervical cancer. The major oncoproteins of these cancer-associated viruses are encoded by the viral E6 and E7 genes. Thorough characterization of these oncoproteins and their interaction with cellular proteins has shown that both E6 and E7 exploit the ubiquitin-proteasome system to degrade and, thus, to functionally inactivate negative cell-regulatory proteins including members of the p110(RB) family and p53. This act of piracy is assumed to contribute to both the efficient propagation of HPVs and HPV-induced carcinogenesis.

  10. Rebamipide attenuates Helicobacter pylori CagA-induced self-renewal capacity via modulation of β-catenin signaling axis in gastric cancer-initiating cells.

    PubMed

    Kang, Dong Woo; Noh, Yu Na; Hwang, Won Chan; Choi, Kang-Yell; Min, Do Sik

    2016-08-01

    Rebamipide, a mucosal-protective agent, is used clinically for treatment of gastritis and peptic ulcers induced by Helicobacter pylori (H. pylori) which is associated with increased risk of gastric cancer. Although rebamipide is known to inhibit the growth of gastric cancer cells, the action mechanisms of rebamipide in gastric carcinogenesis remains elusive. Here, we show that rebamipide suppresses H. pylori CagA-induced β-catenin and its target cancer-initiating cells (C-IC) marker gene expression via upregulation of miRNA-320a and -4496. Rebamipide attenuated in vitro self-renewal capacity of H. pylori CagA-infected gastric C-IC via modulation of miRNA-320a/-4496-β-catenin signaling axis. Moreover, rebamipide enhanced sensitivity to chemotherapeutic drugs in CagA-expressed gastric C-IC. Furthermore, rebamipide suppressed tumor-initiating capacity of gastric C-IC, probably via suppression of CagA-induced C-IC properties. These data provide novel insights for the efficacy of rebamipide as a chemoprotective drug against H. pylori CagA-induced carcinogenic potential. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis

    PubMed Central

    Manils, Joan; Gómez, Diana; Salla-Martret, Mercè; Fischer, Heinz; Fye, Jason M.; Marzo, Elena; Marruecos, Laura; Serrano, Inma; Salgado, Rocío; Rodrigo, Juan P.; Garcia-Pedrero, Juana M.; Serafin, Anna M.; Cañas, Xavier; Benito, Carmen; Toll, Agustí; Forcales, Sònia-Vanina; Perrino, Fred W.; Eckhart, Leopold; Soler, Concepció

    2015-01-01

    TREX2 is a 3′-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response. PMID:26090614

  12. Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.

    PubMed

    Manils, Joan; Gómez, Diana; Salla-Martret, Mercè; Fischer, Heinz; Fye, Jason M; Marzo, Elena; Marruecos, Laura; Serrano, Inma; Salgado, Rocío; Rodrigo, Juan P; Garcia-Pedrero, Juana M; Serafin, Anna M; Cañas, Xavier; Benito, Carmen; Toll, Agustí; Forcales, Sònia-Vanina; Perrino, Fred W; Eckhart, Leopold; Soler, Concepció

    2015-09-08

    TREX2 is a 3'-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response.

  13. Cooked Chickpea Consumption Inhibits Colon Carcinogenesis in Mice Induced with Azoxymethane and Dextran Sulfate Sodium.

    PubMed

    Chino, Xariss M Sánchez; Martínez, Cristian Jiménez; Garzón, Verónica R Vásquez; González, Isela Álvarez; Treviño, Saúl Villa; Bujaidar, Eduardo Madrigal; Ortiz, Gloria Dávila; Hoyos, Rafael Baltiérrez

    2017-07-01

    The objective of the study was to evaluate the effect of daily consumption of cooked chickpea (2% and 10%) in ICR male mice in which colon cancer was induced with azoxymethane and dextran sulfate sodium. The effect of consumption of 2% or 10% cooked chickpeas on carcinogenesis-induced colon azoxymethane (AOM)/dextran sulfate sodium (DSS) in ICR mice was determined. Protein oxidation and lipids were determined by colorimetric methods and oxidation of DNA through the identification of adducts 8-hydroxy-2'-desoxiguanosine and proliferation markers (proliferating cell nuclear antigen [PCNA], Ki-67, and β-catenin), and inflammation (cyclooxygenase [COX]-2 and inducible nitric oxide synthase [iNOS]) were identified by immunohistochemistry reactions. The results showed the protective effect of daily consumption of rich cooked chickpeas in the carcinogenesis process, decreasing lipid, protein, and DNA oxidation and decreasing the expression of inflammatory enzymes (COX-2 and iNOS) as well as β-catenin, one of the most important oncogenic proteins in colon cancer. Animals that were fed with the 10% chickpea diet showed an inhibition in cellular proliferation (Ki-67 and PCNA expression). The addition of cooked chickpea seed (2% and 10%) to the daily diet is proposed as a chemopreventive agent against colon cancer.

  14. In Vivo Analysis of the Viable Microbiota and Helicobacter pylori Transcriptome in Gastric Infection and Early Stages of Carcinogenesis.

    PubMed

    Thorell, Kaisa; Bengtsson-Palme, Johan; Liu, Oscar Hsin-Fu; Palacios Gonzales, Reyna Victoria; Nookaew, Intawat; Rabeneck, Linda; Paszat, Lawrence; Graham, David Y; Nielsen, Jens; Lundin, Samuel B; Sjöling, Åsa

    2017-10-01

    Emerging evidence shows that the human microbiota plays a larger role in disease progression and health than previously anticipated. Helicobacter pylori, the causative agent of gastric cancer and duodenal and gastric ulcers, was early associated with gastric disease, but it has also been proposed that the accompanying microbiota in Helicobacter pylori-infected individuals might affect disease progression and gastric cancer development. In this study, the composition of the transcriptionally active microbial community and H. pylori gene expression were determined using metatranscriptomic RNA sequencing of stomach biopsy specimens from individuals with different H. pylori infection statuses and premalignant tissue changes. The results show that H. pylori completely dominates the microbiota not only in infected individuals but also in most individuals classified as H. pylori uninfected using conventional methods. Furthermore, H. pylori abundance is positively correlated with the presence of Campylobacter, Deinococcus, and Sulfurospirillum Finally, we quantified the expression of a large number of Helicobacter pylori genes and found high expression of genes involved in pH regulation and nickel transport. Our study is the first to dissect the viable microbiota of the human stomach by metatranscriptomic analysis, and it shows that metatranscriptomic analysis of the gastric microbiota is feasible and can provide new insights into how bacteria respond in vivo to variations in the stomach microenvironment and at different stages of disease progression. Copyright © 2017 American Society for Microbiology.

  15. Radiation-induced genomic instability and its implications for radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Huang, Lei; Snyder, Andrew R.; Morgan, William F.

    2003-01-01

    Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

  16. Radiation-induced genomic instability and its implications for radiation carcinogenesis

    NASA Technical Reports Server (NTRS)

    Huang, Lei; Snyder, Andrew R.; Morgan, William F.

    2003-01-01

    Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

  17. Antioxidant activity of apple extract protects against rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide.

    PubMed

    Ribeiro, Flávia Andressa Pidone; Peres, Rogerio Correa; Oshima, Celina Tizuko Fujiyama; Spolidorio, Luiz Carlos; Maluf, Luciana Le Sueur; Ribeiro, Daniel Araki

    2015-01-01

    Several studies have shown that apple (Malus sp.) has many components able to exert chemopreventive activity. The aim of this study was to evaluate the chemopreventive potential of apple extract following medium-term oral carcinogenesis assay induced by 4-nitroquinoline 1-oxide (4NQO) by means of histopathological analysis and gene expression of antioxidant enzymes, such as CuZnSOD, MnSOD and catalase. A total of 30 male Wistar rats were distributed into five groups, as follows (n = 6 per group): Group 1 - negative control group (non-treated group); Group 2 - received 4NQO during 8 weeks in drinking water and treated with apple extract by gavage between the 1st and 4th weeks daily (initiation phase); Group 3 - received 4NQO for 8 weeks in drinking water and treated with apple extract by gavage between the 5th and 8th weeks daily (promotion phase); Group 4 - received apple extract by gavage for eight consecutive weeks only; and Group 5 - received 4NQO for 8 weeks in drinking water daily. Histopathological analysis revealed that apple extract protect oral lesions induced by 4NQO at initiation or promotion phase. Higher gene expression of CuZnSOD and MnSOD enzymes were noticed in groups treated with apple extract as well. Taken together, our results demonstrate that the apple extract is able to modulate medium-term oral carcinogenesis assay as a result of antioxidant activity.

  18. EMODIN DOWNREGULATES CELL PROLIFERATION MARKERS DURING DMBA INDUCED ORAL CARCINOGENESIS IN GOLDEN SYRIAN HAMSTERS.

    PubMed

    Manimaran, Asokan; Buddhan, Rajamanickam; Manoharan, Shanmugam

    2017-01-01

    Cell-cycle disruption is the major characteristic features of neoplastic transformation and the status of cell-cycle regulators can thus be utilized to assess the prognostic significance in patients with cancer. The PCNA, cyclin D1, CDK4, CDK6 and survivin expression in the buccal mucosa was utilized to evaluate the Emodin efficacy on abnormal cell proliferation during 7,12-dimethylbenz(a)anthracene (DMBA) induced oral carcinogenesis in golden Syrian hamsters. Topical application of DMBA, three times a week for 14 weeks, on the hamsters' buccal pouches developed well differentiated squamous cell carcinoma. Cyclin D1 and PCNA over-expression and up-regulation of CDK4, CDK6 and survivin were noticed in the buccal mucosa of hamsters treated with DMBA alone. Emodin administration (50mg/kg b.w) orally to hamsters treated with DMBA down-regulated the expression of cell proliferation markers in the buccal mucosa. The anti-cell proliferative role of Emodin is owing to its modulating efficacy on cell-cycle markers towards the tumor suppression during DMBA induced oral carcinogenesis.

  19. Modulatory activity of Brazilian red propolis on chemically induced dermal carcinogenesis.

    PubMed

    Pinheiro, Kariny Souza; Ribeiro, Danielle Rodrigues; Alves, Angela Valéria Farias; Pereira-Filho, Rose Nely; Oliveira, Clauberto Rodrigues de; Lima, Sônia Oliveira; Reis, Francisco Prado; Cardoso, Juliana Cordeiro; Albuquerque-Júnior, Ricardo Luiz Cavalcanti de

    2014-02-01

    To evaluate modulatory effects of a hydroalcoholic extract of Brazilian red propolis (HERP) on dermal carcinogenesis using a murine model. The HERP was used at concentrations of 10, 50 and 100 mg/kg (PROP10, PROP50 and PROP100, respectively) to modulate dermal carcinogenesis induced by the application of 9,10-dimetil-1,2-benzatraceno (DMBA) on the backs of animals. The chemical compounds identified in HERP included propyl gallate, catechin, epicatechin and formononetin. PROP100 treatment resulted in significantly decreased tumor multiplicity throughout the five weeks of tumor promotion (p<0.05), and this concentration also resulted in the highest frequency of verrucous tumors (p<0.05). All of the tumors that developed in DMBA-treated animals were regarded as squamous cell carcinomas and were either diagnosed as non-invasive verrucous carcinomas or invasive squamous cell carcinomas (SCCs). The average score for malignancy was significantly lower in the PROP100-treated group than the non-treated group (p<0.05), but there was no difference between the other groups (p>0.05). The oral administration of hydroalcoholic extract of Brazilian red propolis at a dose of 100 mg/kg had a significant modulatory effect on the formation, differentiation and progression of chemically induced squamous cell carcinoma in a murine experimental model.

  20. Effects of adlay on azoxymethane-induced colon carcinogenesis in rats.

    PubMed

    Shih, Chun-Kuang; Chiang, Wenchang; Kuo, Min-Liang

    2004-08-01

    Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) is a grass crop used in traditional Chinese medicine and as a nutritious food. It has been reported that adlay has anti-inflammatory and anti-tumor activity. Cyclooxygenase-2 (COX-2) is an inducible enzyme functionally related to both inflammation and colon carcinogenesis and is the target of many chemopreventive agents. This study investigated the effect of adlay on colon carcinogenesis and COX-2 expression. In a short-term experiment, male F344 rats were fed diets containing different doses of dehulled adlay and received the colon-specific carcinogen, azoxymethane (AOM), by intraperitoneal injection. All rats were killed after 5 weeks of feeding, and the colons were examined for the preneoplastic lesion, aberrant crypt foci (ACF). Dietary dehulled adlay at levels of 10%, 20%, or 40% significantly reduced the numbers of ACF and aberrant crypts. Dehulled adlay reduced the number of ACF of different sizes but did not affect the crypt multiplicity. Most ACF were found in the middle and distal colons; dehulled adlay significantly suppressed the formation of ACF in the middle colon. In a long-term experiment, male F344 rats were fed diets containing different doses of dehulled adlay and injected with AOM. All rats were killed after 52 weeks of feeding, and colons were examined for tumors and COX-2 protein expression. The results indicated that dehulled adlay did not inhibit colon tumors in spite of a slight suppressing effect in the proximal colon. Rats fed diets containing 20% dehulled adlay had less COX-2 protein expression in both proximal and distal colon tumors. The inconsistent effects between COX-2 protein expression and tumor outcome may be due to regional differences in the colon and the malignancy of the tumors. These findings suggest that dehulled adlay suppresses early events in colon carcinogenesis but not the formation of tumors.

  1. Effect of light/dark regimen on N-nitrosoethylurea-induced transplacental carcinogenesis in rats.

    PubMed

    Beniashvili, D S; Benjamin, S; Baturin, D A; Anisimov, V N

    2001-02-10

    Pregnant females were randomly subdivided into three groups (24 rats per group) and kept at the 12:12 h light/dark regimen (group 1), at the constant light illumination (24 h a day, group 2) or at the continuous darkness (group 3). N-nitrosoethylurea (NEU) has been injected into the tail vein of all rats (80 mg/kg) on the 18-19th day of the pregnancy. After the delivery the lacting dams and their progeny during the lactation period (1 month after delivery) were kept also at the three different light/dark regimens. Then all offspring from each group was kept at the 12:12 h light/dark regimen, males and females separately, and were observed until natural death. The exposure to constant light significantly promoted the transplacental carcinogenesis whereas the exposure to constant darkness inhibited it. The incidence of total tumors, tumors of both a peripheral nervous system and kidney was 2.6; 2.5 and 8.5 times higher, and survival significantly shorter, correspondingly, in rats from the group 2 exposed to the constant light regimen as compared to the group 1 (12:12 h light/dark regimen) (P<0.05). On the other hand, the exposure to the continuous darkness during the pregnancy and the lactation period significantly inhibited the transplacental carcinogenesis in the offspring of rats treated with NEU. The incidence of total tumors, tumors of a peripheral nervous system was by 2.4 and 2.7 times less, and survival longer, respectively, in exposed to the darkness rats from the group 3 as compared to the group 1 (12:12 h light/dark regimen) (P<0.05). Thus, our data firstly have shown the modifying effect of light-dark regimen on the realization of the transplacental carcinogenesis induced by NEU in rats.

  2. Gastric Metaplasia Induced by Helicobacter pylori Is Associated with Enhanced SOX9 Expression via Interleukin-1 Signaling.

    PubMed

    Serizawa, Takako; Hirata, Yoshihiro; Hayakawa, Yoku; Suzuki, Nobumi; Sakitani, Kosuke; Hikiba, Yohko; Ihara, Sozaburo; Kinoshita, Hiroto; Nakagawa, Hayato; Tateishi, Keisuke; Koike, Kazuhiko

    2015-12-07

    Histopathological changes of the gastric mucosa after Helicobacter pylori infection, such as atrophy, metaplasia, and dysplasia, are considered to be precursors of gastric cancer, yet the mechanisms of histological progression are unknown. The aim of this study was to analyze the histopathological features of the gastric mucosa in mice infected with H. pylori strain PMSS1 in relation to gastric stem cell marker expression. C57BL/6J mice infected with PMSS1 were examined for histopathological changes, levels of proinflammatory cytokines, and expression of stem cell markers. Histopathological gastritis scores, such as atrophy and metaplasia, and levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β), were increased after PMSS1 infection. Expression levels of the cell proliferation and stem cell markers CD44 and SOX9 were also significantly increased in PMSS1-infected mice. Importantly, almost all metaplastic cells induced by PMSS1 infection expressed SOX9. When IL-1 receptor (IL-1R) knockout mice were infected with PMSS1, metaplastic changes and expression levels of stem cell markers were significantly decreased compared with those in wild-type (WT) mice. In conclusion, H. pylori infection induced the expression of cytokines and stem cell markers and histopathological metaplasia in the mouse gastric mucosa. SOX9 expression, in particular, was strongly associated with metaplastic changes, and these changes were dependent on IL-1 signaling. The results suggested the importance of SOX9 in gastric carcinogenesis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  3. The Role of Oxidative Stress in Carcinogenesis Induced by Metals and Xenobiotics

    PubMed Central

    Henkler, Frank; Brinkmann, Joep; Luch, Andreas

    2010-01-01

    In addition to a wide range of adverse effects on human health, toxic metals such as cadmium, arsenic and nickel can also promote carcinogenesis. The toxicological properties of these metals are partly related to generation of reactive oxygen species (ROS) that can induce DNA damage and trigger redox-dependent transcription factors. The precise mechanisms that induce oxidative stress are not fully understood. Further, it is not yet known whether chronic exposures to low doses of arsenic, cadmium or other metals are sufficient to induce mutations in vivo, leading to DNA repair responses and/or tumorigenesis. Oxidative stress can also be induced by environmental xenobiotics, when certain metabolites are generated that lead to the continuous release of superoxide, as long as the capacity to reduce the resulting dions (quinones) into hydroquinones is maintained. However, the specific significance of superoxide-dependent pathways to carcinogenesis is often difficult to address, because formation of DNA adducts by mutagenic metabolites can occur in parallel. Here, we will review both mechanisms and toxicological consequences of oxidative stress triggered by metals and dietary or environmental pollutants in general. Besides causing DNA damage, ROS may further induce multiple intracellular signaling pathways, notably NF-κB, JNK/SAPK/p38, as well as Erk/MAPK. These signaling routes can lead to transcriptional induction of target genes that could promote proliferation or confer apoptosis resistance to exposed cells. The significance of these additional modes depends on tissue, cell-type and is often masked by alternate oncogenic mechanisms being activated in parallel. PMID:24281075

  4. Caryocar brasiliense camb protects against genomic and oxidative damage in urethane-induced lung carcinogenesis

    PubMed Central

    Colombo, N.B.R.; Rangel, M.P.; Martins, V.; Hage, M.; Gelain, D.P.; Barbeiro, D.F.; Grisolia, C.K.; Parra, E.R.; Capelozzi, V.L.

    2015-01-01

    The antioxidant effects of Caryocar brasiliense Camb, commonly known as the pequi fruit, have not been evaluated to determine their protective effects against oxidative damage in lung carcinogenesis. In the present study, we evaluated the role of pequi fruit against urethane-induced DNA damage and oxidative stress in forty 8-12 week old male BALB/C mice. An in vivo comet assay was performed to assess DNA damage in lung tissues and changes in lipid peroxidation and redox cycle antioxidants were monitored for oxidative stress. Prior supplementation with pequi oil or its extract (15 µL, 60 days) significantly reduced urethane-induced oxidative stress. A protective effect against DNA damage was associated with the modulation of lipid peroxidation and low protein and gene expression of nitric oxide synthase. These findings suggest that the intake of pequi fruit might protect against in vivo genotoxicity and oxidative stress. PMID:26200231

  5. Effects of nobiletin on PhIP-induced prostate and colon carcinogenesis in F344 rats.

    PubMed

    Tang, Ming Xi; Ogawa, Kumiko; Asamoto, Makoto; Chewonarin, Teera; Suzuki, Shugo; Tanaka, Takuji; Shirai, Tomoyuki

    2011-01-01

    The current study was designed to investigate the effects of nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced prostate and colon carcinogenesis. PhIP was administered to 6-wk-old F344 male rats intragastrically (100 mg/kg) twice a wk for 10 wk. The animals were given 0.05% nobiletin or the basal diet for 50 wk. At the end of the experiment, serum testosterone, estrogen, and leptin did not differ between the 2 groups. The body weights of nobiletin-treated rats were significantly higher than controls (P<0.05), and feeding of nobiletin significantly reduced the relative prostate (P<0.05) and testes (P<0.05) weights as well as the Ki67 labeling index in the normal epithelium in the ventral prostate (P<0.01). The incidence and multiplicity of adenocarcinomas in nobiletin-treated ventral prostate were 50% and 36%, respectively, of controls, but the differences were not statistically significant. However, nobiletin did significantly reduce the total number of colonic aberrant crypt foci (ACF) compared to the control value (P<0.05). Nobiletin, therefore, may have potential for chemoprevention of early changes associated with carcinogenesis in both the prostate and colon.

  6. Dark field optical imaging reveals vascular changes in an inducible hamster cheek pouch model during carcinogenesis

    PubMed Central

    Hu, Fangyao; Morhard, Robert; Murphy, Helen A.; Zhu, Caigang; Ramanujam, Nimmi

    2016-01-01

    In this study, we propose a low-cost cross-polarized dark field microscopy system for in vivo vascular imaging to detect head and neck cancer. A simple-to-use Gabor-filter-based image processing technique was developed to objectively and automatically quantify several important vascular features, including tortuosity, length, diameter and area fraction, from vascular images. Simulations were performed to evaluate the accuracies of vessel segmentation and feature extraction for our algorithm. Sensitivity and specificity for vessel segmentation of the Gabor masks both remained above 80% at all contrast levels when compared to gold-standard masks. Errors for vascular feature extraction were under 5%. Moreover, vascular contrast and vessel diameter were identified to be the two primary factors which affected the segmentation accuracies. After our algorithm was validated, we monitored the blood vessels in an inducible hamster cheek pouch carcinogen model over 17 weeks and quantified vascular features during carcinogenesis. A significant increase in vascular tortuosity and a significant decrease in vessel length were observed during carcinogenesis. PMID:27699096

  7. The balance between initiation and promotion in radiation-induced murine carcinogenesis.

    PubMed

    Shuryak, Igor; Ullrich, Robert L; Sachs, Rainer K; Brenner, David J

    2010-09-01

    Studies of radiation carcinogenesis in animals allow detailed investigation of how the risk depends on age at exposure and time since exposure and of the mechanisms that determine this risk, e.g., induction of new pre-malignant cells (initiation) and enhanced proliferation of already existing pre-malignant cells (promotion). To assist the interpretation of these patterns, we apply a newly developed biologically based mathematical model to data on several types of solid tumors induced by acute whole-body radiation in mice. The model includes both initiation and promotion and analyzes pre-malignant cell dynamics on two different time scales: comparatively short-term during irradiation and long-term during the entire life span. Our results suggest general mechanistic similarities between radiation carcinogenesis in mice and in human atomic bomb survivors. The excess relative risk (ERR) in mice decreases with age at exposure up to an exposure age of 1 year, which corresponds to mid-adulthood in humans; the pattern for older ages at exposure, for which there is some evidence of increasing ERRs in atomic bomb survivors, cannot be evaluated using the data set analyzed here. Also similar to findings in humans, initiation dominates the ERR at young ages in mice, when there are few background pre-malignant cells, and promotion becomes important at older ages.

  8. The Balance Between Initiation and Promotion in Radiation-Induced Murine Carcinogenesis

    PubMed Central

    Shuryak, Igor; Ullrich, Robert L.; Sachs, Rainer K.; Brenner, David J.

    2013-01-01

    Studies of radiation carcinogenesis in animals allow detailed investigation of how the risk depends on age at exposure and time since exposure and of the mechanisms that determine this risk, e.g., induction of new pre-malignant cells (initiation) and enhanced proliferation of already existing pre-malignant cells (promotion). To assist the interpretation of these patterns, we apply a newly developed biologically based mathematical model to data on several types of solid tumors induced by acute whole-body radiation in mice. The model includes both initiation and promotion and analyzes pre-malignant cell dynamics on two different time scales: comparatively short-term during irradiation and long-term during the entire life span. Our results suggest general mechanistic similarities between radiation carcinogenesis in mice and in human atomic bomb survivors. The excess relative risk (ERR) in mice decreases with age at exposure up to an exposure age of 1 year, which corresponds to mid-adulthood in humans; the pattern for older ages at exposure, for which there is some evidence of increasing ERRs in atomic bomb survivors, cannot be evaluated using the data set analyzed here. Also similar to findings in humans, initiation dominates the ERR at young ages in mice, when there are few background pre-malignant cells, and promotion becomes important at older ages. PMID:20726716

  9. High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells.

    PubMed

    Kato, Sosuke; Tsukamoto, Tetsuya; Mizoshita, Tsutomu; Tanaka, Harunari; Kumagai, Toshiko; Ota, Hiroyoshi; Katsuyama, Tsutomu; Asaka, Masahiro; Tatematsu, Masae

    2006-10-01

    Intake of salt and salty food is known as a risk factor for gastric carcinogenesis. To examine the dose-dependence and the mechanisms underlying enhancing effects, Mongolian gerbils were treated with N-methyl-N-nitrosourea (MNU), Helicobacter pylori and food containing various concentrations of salt, and were sacrificed after 50 weeks. Among gerbils treated with MNU and H. pylori, the incidences of glandular stomach cancers were 15% in the normal diet group and 33%, 36% and 63% in the 2.5%, 5% and 10% NaCl diet groups, showing dose-dependent increase (p < 0.01). Intermittent intragastric injection of saturated NaCl solution, in contrast, did not promote gastric carcinogenesis. In gerbils infected with H. pylori, a high salt diet was associated with elevation of anti-H. pylori antibody titers, serum gastrin levels and inflammatory cell infiltration in a dose-dependent fashion. Ten percent NaCl diet upregulated the amount of surface mucous cell mucin (p < 0.05), suitable for H. pylori colonization, despite no increment of MUC5AC mRNA, while H. pylori infection itself had an opposing effect, stimulating transcription of MUC6 and increasing the amount of gland mucous cell mucin (GMCM). High salt diet, in turn, decreased the amount of GMCM, which acts against H. pylori infection. In conclusion, the present study demonstrated dose-dependent enhancing effects of salt in gastric chemical carcinogenesis in H. pylori-infected Mongolian gerbils associated with alteration of the mucous microenvironment. Reduction of salt intake could thus be one of the most important chemopreventive methods for human gastric carcinogenesis.

  10. Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine production.

    PubMed

    Chew, Shan Hwu; Okazaki, Yasumasa; Nagai, Hirotaka; Misawa, Nobuaki; Akatsuka, Shinya; Yamashita, Kyoko; Jiang, Li; Yamashita, Yoriko; Noguchi, Michio; Hosoda, Kiminori; Sekido, Yoshitaka; Takahashi, Takashi; Toyokuni, Shinya

    2014-01-01

    Like many other human cancers, the development of malignant mesothelioma is closely associated with a chronic inflammatory condition. Both macrophages and mesothelial cells play crucial roles in the inflammatory response caused by asbestos exposure. Here, we show that adipocytes can also contribute to asbestos-induced inflammation through dysregulated adipocytokine production. 3T3-L1 preadipocytes were differentiated into mature adipocytes prior to use. These cells took up asbestos fibers (chrysotile, crocidolite and amosite) but were more resistant to asbestos-induced injury than macrophages and mesothelial cells. Expression microarray analysis followed by reverse transcription-PCR revealed that adipocytes respond directly to asbestos exposure with an increased production of proinflammatory adipocytokines [e.g. monocyte chemoattractant protein-1 (MCP-1)], whereas the production of anti-inflammatory adipocytokines (e.g. adiponectin) is suppressed. This was confirmed in epididymal fat pad of mice after intraperitoneal injection of asbestos fibers. Such dysregulated adipocytokine production favors the establishment of a proinflammatory environment. Furthermore, MCP-1 marginally promoted the growth of MeT-5A mesothelial cells and significantly enhanced the wound healing of Y-MESO-8A and Y-MESO-8D human mesothelioma cells. Our results suggest that increased levels of adipocytokines, such as MCP-1, can potentially contribute to the promotion of mesothelial carcinogenesis through the enhanced recruitment of inflammatory cells as well as a direct growth and migration stimulatory effect on mesothelial and mesothelioma cells. Taken together, our findings support a potential cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis.

  11. Matrix metalloproteinase 7 restrains Helicobacter pylori-induced gastric inflammation and premalignant lesions in the stomach by altering macrophage polarization.

    PubMed

    Krakowiak, M S; Noto, J M; Piazuelo, M B; Hardbower, D M; Romero-Gallo, J; Delgado, A; Chaturvedi, R; Correa, P; Wilson, K T; Peek, R M

    2015-04-02

    Helicobacter pylori is the strongest risk factor for the development of gastric cancer. Although the specific mechanisms by which this pathogen induces carcinogenesis have not been fully elucidated, high-expression interleukin (IL)-1β alleles are associated with increased gastric cancer risk among H. pylori-infected persons. In addition, loss of matrix metalloproteinase 7 (MMP7) increases mucosal inflammation in mouse models of epithelial injury, and we have shown that gastric inflammation is increased in H. pylori-infected MMP7(-/-) C57BL/6 mice. In this report, we define mechanisms that underpin such responses and extend these results into a genetic model of MMP7 deficiency and gastric cancer. Wild-type (WT) or MMP7(-/-) C57BL/6 mice were challenged with broth alone as an uninfected control or the H. pylori strain PMSS1. All H. pylori-challenged mice were successfully colonized. As expected, H. pylori-infected MMP7(-/-) C57BL/6 mice exhibited a significant increase in gastric inflammation compared with uninfected or infected WT C57BL/6 animals. Loss of MMP7 resulted in M1 macrophage polarization within H. pylori-infected stomachs, as assessed by Luminex technology and immunohistochemistry, and macrophages isolated from infected MMP7-deficient mice expressed significantly higher levels of the M1 macrophage marker IL-1β compared with macrophages isolated from WT mice. To extend these findings into a model of gastric cancer, hypergastrinemic WT INS-GAS or MMP7(-/-) INS-GAS mice were challenged with H. pylori strain PMSS1. Consistent with findings in the C57BL/6 model, H. pylori-infected MMP7-deficient INS-GAS mice exhibited a significant increase in gastric inflammation compared with either uninfected or infected WT INS-GAS mice. In addition, the incidence of gastric hyperplasia and dysplasia was significantly increased in H. pylori-infected MMP7(-/-) INS-GAS mice compared with infected WT INS-GAS mice, and loss of MMP7 promoted M1 macrophage polarization. These

  12. D-pinitol mitigates tumor growth by modulating interleukins and hormones and induces apoptosis in rat breast carcinogenesis through inhibition of NF-κB.

    PubMed

    Rengarajan, Thamaraiselvan; Nandakumar, Natarajan; Rajendran, Peramaiyan; Ganesh, Mohanraj Karthik; Balasubramanian, Maruthaiveeran Periyasamy; Nishigaki, Ikuo

    2015-06-01

    Breast cancer is the most prevalent malignant neoplasm in the world, and chemoprevention through dietary intervention strategy is an emerging option to reduce the incidence. D-pinitol (DP), a major component of soya bean, possesses attractive biological actions. We have investigated whether D-pinitol have an effect on tumor growth in vivo against 7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary carcinogenesis and investigated its mechanism of action. Tumors were induced in Sprague-Dawley (SD) rats by a gastric dose of 20 mg/kg DMBA, and after 13 weeks of induction period, the rats were orally administered with D-pinitol for 45 days. At the end of the assay, animals in carcinogen control group prompted a tumor incidence of 100 % and developed a tumor volume of 8.35 ± 0.56, which was significantly reduced to 5.74 ± 0.32 for the animals treated with D-pinitol. The D-pinitol treatment not only decreased the tumor volume but also further examination revealed that tumors from animals that received D-pinitol reduced nuclear factor kappa B (NF-κB) activation which in turn results in modulation of its downstreaming p53 and proteins of caspase-3 family. Bcl-2 expression and caspase-3 activation were also decreased after D-pinitol supplementation leading to induction of apoptosis and finally cell death. Furthermore, the status of the inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-2, IL-6, and tumor markers, lipid profile, and hormones was also significantly declined up on D-pinitol administration. Thus, it reveals the collective involvement of the above-mentioned parameters along with NF-κB signaling through which D-pinitol induces apoptosis and subsequently suppresses breast cancer during DMBA-induced rat breast carcinogenesis.

  13. Role of neutrophils in acrylonitrile-induced gastric mucosal damage.

    PubMed

    Hamdy, Nadia M; Al-Abbasi, Fahad A; Alghamdi, Hassan A; Tolba, Mai F; Esmat, Ahmed; Abdel-Naim, Ashraf B

    2012-01-25

    Acrylonitrile (ACN) is a widely used intermediate in the manufacture of plastics, acrylic fibers, synthetic rubbers and resins that are used in a variety of products including food containers and medical devices. ACN is a possible human carcinogen and a documented animal carcinogen, with the stomach being an important target of its toxicity. ACN has been previously reported to require metabolic activation to reactive intermediates and finally to cyanide (CN⁻). The current study aimed at exploring the potential role of neutrophils in ACN-induced gastric damage in rats. Experimental neutropenia was attained by injecting rats with methotrexate. This significantly ameliorated gastric mucosal injury induced by ACN. This is evidenced by protection against the increase in gastric ulcer index, myeloperoxidase (MPO) activity and CN⁻ level. Also, neutropenia guarded against the decrease in prostaglandin E2 (PGE2), induction of oxidative stress and reduction of total nitrites and alleviated histopathological alterations in rat stomachs. These data indicate that neutrophil infiltration is, at least partly, involved in ACN-induced gastric damage in rats.

  14. Toxicogenomic Effects in Rat Blood Leukocytes and Chemoprophylaxis of Radiation-Induced Carcinogenesis.

    PubMed

    Ivanov, S D; Bespalov, V G; Semenov, A L; Kovan'ko, E G; Aleksandrov, V A

    2016-03-01

    Toxicogenomic parameters were studied in the blood of female rats after exposure to ionizing γ-radiation in a dose of 4 Gy and chemoprophylaxis with α-difluoromethylornithine, eleutherococcus or leuzea extracts, which were used in animals with morphological manifestations of tumor growth under conditions of radiation-induced carcinogenesis. Life-time evaluation of toxicogenomic effects was carried out by express method for measurements of blood nucleotid DNA - fluorescent indication. The level of hyperaneu/polyploidy increased in the blood leukocytes of control rats 30 days after radiation exposure. A significant decrease of genotoxicity as a result of drug treatment in comparison with the number and multiplicity of tumors in irradiated animals was found only in the endocrine and reproductive organs of rats treated by eleutherococcus extract.

  15. URI prevents potassium dichromate-induced oxidative stress and cell death in gastric cancer cells

    PubMed Central

    Luo, Dongwei; Xu, Zhonghai; Hu, Xiaoxia; Zhang, Fei; Bian, Huiqin; Li, Na; Wang, Qian; Lu, Yaojuan; Zheng, Qiping; Gu, Junxia

    2016-01-01

    Chromium VI can provoke oxidative stress, DNA damage, cytotoxicity, mutagenesis and carcinogenesis. Aberrantly high level of reactive oxygen species (ROS) has been associated with oxidative stress and subsequent DNA damage. Notably, multiple previous studies have shown the increased level of ROS in chromium (VI) induced oxidative stress, but its effect on cell death and the underlying mechanism remain to be determined. In this study, we aimed to investigate the role of URI, an unconventional prefoldin RBP5 interactor, in potassium dichromate induced oxidative stress and cell death through in vitro loss-of-function studies. We have shown that knockdown of URI in human gastric cancer SGC-7901 cells by URI siRNA enhanced potassium dichromate-induced production of ROS. The level of rH2AX, a marker of DNA damage, was significantly increased, along with a reduced cell viability in URI siRNA treated cells that were also exposed to potassium dichromate. Comet assay showed that URI knockdown increased the tail moment in potassium dichromate-treated SGC-7901 cells. Accordingly, the cell rates of apoptosis and necrosis were also increased in URI knockdown cells treated with potassium dichromate at different concentrations. Together, these results suggest that URI is preventive for the oxidative stress and cell death induced by potassium dichromate, which potentially leads to cancer cell survival and therapeutic resistance. PMID:28078011

  16. IDENTIFICATION OF THE ROLE OF APOPTOSIS PATHWAYS POTENTIALLY INVOLVED IN FORMALDEHYDE-INDUCED CARCINOGENESIS USING CDNA ARRAYS

    EPA Science Inventory

    Identification of the Role of Apoptosis Pathways Potentially Involved in Formaldehyde- Induced Carcinogenesis Using cDNA Arrays.

    Formaldehyde (FA) is a genotoxic chemical found in household, medicinal, and industrial products. Although the major source of human exposure is...

  17. IDENTIFICATION OF THE ROLE OF APOPTOSIS PATHWAYS POTENTIALLY INVOLVED IN FORMALDEHYDE-INDUCED CARCINOGENESIS USING CDNA ARRAYS

    EPA Science Inventory

    Identification of the Role of Apoptosis Pathways Potentially Involved in Formaldehyde- Induced Carcinogenesis Using cDNA Arrays.

    Formaldehyde (FA) is a genotoxic chemical found in household, medicinal, and industrial products. Although the major source of human exposure is...

  18. Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis.

    PubMed

    Wang, Li-Jing; Zhao, Yuan; Han, Bing; Ma, Yu-Guang; Zhang, Jie; Yang, Ding-Ming; Mao, Jian-Wen; Tang, Fu-Tian; Li, Wei-Dong; Yang, Yang; Wang, Rui; Geng, Jian-Guo

    2008-03-01

    Slit is a secreted protein known to function through the Roundabout (Robo) receptor as a repellent for axon guidance and neuronal migration, and as an inhibitor in leukocyte chemotaxis. We have previously shown that Slit2 is also secreted by a variety of human cancer cells whereby it acts as a chemoattractant to vascular endothelial cells for tumor angiogenesis. We used a blocking antibody to investigate the role of Slit-Robo signaling in tumor angiogenesis during oral carcinogenesis. In this report we undertook a multistage model of 7,12-dimethyl-1,2-benzanthracene-induced squamous cell carcinoma in the hamster buccal pouch. R5, a monoclonal antibody against the first immunoglobulin domain of Robo1, was used to study whether R5 blocks the Slit-Robo interaction and furthermore inhibits tumor angiogenesis and growth in our model. In addition, the expression of Slit2, von Willebrand factor, and vascular endothelial growth factor were examined using human tissue of oral cheek mucosa with oral squamous cell carcinoma. Our data showed that Slit2 was expressed minimally in normal and hyperplastic mucosa, moderately in dysplastic mucosa, and highly in neoplastic mucosa obtained from hamster buccal pouch. We also found that increased Slit2 expression was associated with higher tumor angiogenesis, as reflected by increased vascular endothelial growth factor expression and microvessel density. A similar Slit2 expression profile was found in human tissue. Importantly, interruption of the Slit2-Robo interaction using R5 inhibited tumor angiogenesis and growth in our in vivo model, which indicates that Slit2-mediated tumor angiogenesis is a critical process underlying the carcinogenesis of chemical-induced squamous cell carcinoma. Therefore, targeting Slit-Robo signaling may offer a novel antiangiogenesis approach for oral cancer therapy.

  19. Chemopreventive effect of sinapic acid on 1,2-dimethylhydrazine-induced experimental rat colon carcinogenesis.

    PubMed

    Balaji, C; Muthukumaran, J; Nalini, N

    2014-12-01

    Sinapic acid (SA) is a naturally occurring phenolic acid found in various herbal plants which is attributed with numerous pharmacological properties. This study was aimed to investigate the chemopreventive effect of SA on 1,2-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. Rats were treated with DMH injections (20 mg kg(-1) bodyweight (b.w.) subcutaneously once a week for the first 4 consecutive weeks and SA (20, 40 and 80 mg kg(-1) b.w.) post orally for 16 weeks. At the end of the 16-week experimental period, all the rats were killed, and the tissues were evaluated biochemically. Our results reveal that DMH alone treatment decreased the levels/activities of lipid peroxidation by-products such as thiobarbituric acid reactive substances, conjugated dienes and antioxidants such as superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and reduced glutathione in the intestine and colonic tissues which were reversed on supplementation with SA. Moreover, the activities of drug-metabolizing enzymes of phase I (cytochrome P450 and P4502E1) were enhanced and those of phase II (glutathione-S-transferase, DT-diaphorase and uridine diphosphate glucuronosyl transferase) were diminished in the liver and colonic mucosa of DMH alone-treated rats and were reversed on supplementation with SA. All the above changes were supported by the histopathological observations of the rat liver and colon. These findings suggest that SA at the dose of 40 mg kg(-1) b.w. was the most effective dose against DMH-induced colon carcinogenesis, and thus, SA could be used as a potential chemopreventive agent.

  20. Thrombospondin-2 overexpression in the skin of transgenic mice reduces the susceptibility to chemically-induced multistep skin carcinogenesis

    PubMed Central

    Kunstfeld, Rainer; Hawighorst, Thomas; Streit, Michael; Hong, Young-Kwon; Nguyen, Lynh; Brown, Lawrence F.; Detmar, Michael

    2014-01-01

    Background We have previously reported stromal upregulation of the endogenous angiogenesis inhibitor thrombospondin-2 (TSP-2) during multistep carcinogenesis, and we found accelerated and enhanced skin angiogenesis and carcinogenesis in TSP-2 deficient mice. Goals To investigate whether enhanced levels of TSP-2 might protect from skin cancer development. Methods We established transgenic mice with targeted overexpression of TSP-2 in the skin and subjected hemizygous TSP-2 transgenic mice and their wild-type littermates to a chemical skin carcinogenesis regimen. Results TSP-2 transgenic mice showed a significantly delayed onset of tumor formation compared to wild-type mice, whereas the ratio of malignant conversion to squamous cell carcinomas was comparable in both genotypes. Computer-assisted morphometric analysis of blood vessels revealed pronounced tumor angiogenesis already in the early stages of carcinogenesis in wild type mice. TSP-2 overexpression significantly reduced tumor blood vessel density in transgenic mice but had no overt effect on LYVE-1 positive lymphatic vessels. The percentage of desmin surrounded, mature tumor-associated blood vessels and the degree of epithelial differentiation remained unaffected. The antiangiogenic effect of transgenic TSP-2 was accompanied by a significantly increased number of apoptotic tumor cells in transgenic mice. Conclusion Our results demonstrate that enhanced levels of TSP-2 in the skin result in reduced susceptibility to chemically-induced skin carcinogenesis and identify TSP-2 as a new target for the prevention of skin cancer. PMID:24507936

  1. Green and black tea inhibit cytokine-induced IL-8 production and secretion in AGS gastric cancer cells via inhibition of NF-κB activity.

    PubMed

    Gutierrez-Orozco, Fabiola; Stephens, Brian R; Neilson, Andrew P; Green, Rodney; Ferruzzi, Mario G; Bomser, Joshua A

    2010-10-01

    Consumption of tea is associated with a reduced risk for several gastrointestinal cancers. Inflammatory processes, such as secretion of IL-8 from the gastric epithelium in response to chronic chemokine or antigen exposure, serve both as a chemoattractant for white blood cells and a prerequisite for gastric carcinogenesis. In this study, the gastric adenocarcinoma cell line AGS was used to investigate the effect of green tea extract, black tea extract, and epigallocatechin gallate (EGCG), the most abundant catechin in tea, on cytokine-induced inflammation. AGS cells were stimulated with interleukin-1β (IL-1β) to initiate inflammation, followed by exposure to either tea extracts or EGCG. We found that both green and black tea extracts at concentrations of 20 and 2 µM total catechins, respectively, significantly (p < 0.05) inhibited IL-1β-induced IL-8 production and secretion to a similar extent. Treatment of AGS cells with EGCG (8 µM) produced similar reductions in IL-1β-induced IL-8 production and secretion. Inhibition of NF-κB activity was found to be responsible, in part, for these observed effects. Our findings demonstrate that both green and black tea extracts with distinctly different catechin profiles, are capable of disrupting the molecular link between inflammation and carcinogenesis via inhibition of NF-κB activity in AGS cells.

  2. Nucleosomes Correlate with In Vivo Progression Pattern of De Novo Methylation of p16 CpG Islands in Human Gastric Carcinogenesis

    PubMed Central

    Lu, Zhe-Ming; Zhou, Jing; Wang, Xiuhong; Guan, Zhenpo; Bai, Hua; Liu, Zhao-Jun; Su, Na; Pan, Kaifeng; Ji, Jiafu; Deng, Dajun

    2012-01-01

    Background The exact relationship between nucleosome positioning and methylation of CpG islands in human pathogenesis is unknown. Methodology/Principal Findings In the present study, we characterized the nucleosome position within the p16 CpG island and established a seeding methylation-specific PCR (sMSP) assay based on bisulfite modification to enrich the p16 alleles containing methylated-CpG at the methylation “seeding" sites within its intron-1 in gastric carcinogenesis. The sMSP-positive rate in primary gastric carcinoma (GC) samples (36/40) was significantly higher than that observed in gastritis (19/45) or normal samples (7/13) (P<0.01). Extensive clone sequencing of these sMSP products showed that the density of methylated-CpGs in p16 CpG islands increased gradually along with the severity of pathological changes in gastric tissues. In gastritis lesions the methylation was frequently observed in the region corresponding to the exon-1 coding-nucleosome and the 5′UTR-nucleosome; the methylation was further extended to the region corresponding to the promoter-nucleosome in GC samples. Only few methylated-CpG sites were randomly detected within p16 CpG islands in normal tissues. The significantly inversed relationship between the p16 exon-1 methylation and its transcription was observed in GC samples. An exact p16 promoter-specific 83 bp-MSP assay confirms the result of sMSP (33/55 vs. 1/6, P<0.01). In addition, p16 methylation in chronic gastritis lesions significantly correlated with H. pylori infection; however, such correlation was not observed in GC specimens. Conclusions/Significance It was determined that de novo methylation was initiated in the coding region of p16 exon-1 in gastritis, then progressed to its 5′UTR, and ultimately to the proximal promoter in GCs. Nucleosomes may function as the basic extension/progression unit of de novo methylation of p16 CpG islands in vivo. PMID:22558275

  3. QKI5-mediated alternative splicing of the histone variant macroH2A1 regulates gastric carcinogenesis

    PubMed Central

    Li, Feng; Yi, Ping; Pi, Jingnan; Li, Lanfang; Hui, Jingyi; Wang, Fang; Liang, Aihua; Yu, Jia

    2016-01-01

    Alternative pre-mRNA splicing is a key mechanism for increasing proteomic diversity and modulating gene expression. Emerging evidence indicated that the splicing program is frequently dysregulated during tumorigenesis. Cancer cells produce protein isoforms that can promote growth and survival. The RNA-binding protein QKI5 is a critical regulator of alternative splicing in expanding lists of primary human tumors and tumor cell lines. However, its biological role and regulatory mechanism are poorly defined in gastric cancer (GC) development and progression. In this study, we demonstrated that the downregulation of QKI5 was associated with pTNM stage and pM state of GC patients. Re-introduction of QKI5 could inhibit GC cell proliferation, migration, and invasion in vitro and in vivo, which might be due to the altered splicing pattern of macroH2A1 pre-mRNA, leading to the accumulation of macroH2A1.1 isoform. Furthermore, QKI5 could inhibit cyclin L1 expression via promoting macroH2A1.1 production. Thus, this study identified a novel regulatory axis involved in gastric tumorigenesis and provided a new strategy for GC therapy. PMID:27092877

  4. Chestnut extract induces apoptosis in AGS human gastric cancer cells.

    PubMed

    Lee, Hyun Sook; Kim, Eun Ji; Kim, Sun Hyo

    2011-06-01

    In Korea, chestnut production is increasing each year, but consumption is far below production. We investigated the effect of chestnut extracts on antioxidant activity and anticancer effects. Ethanol extracts of raw chestnut (RCE) or chestnut powder (CPE) had dose-dependent superoxide scavenging activity. Viable numbers of MDA-MD-231 human breast cancer cells, DU145 human prostate cancer cells, and AGS human gastric cancer cells decreased by 18, 31, and 69%, respectively, following treatment with 200 µg/mL CPE for 24 hr. CPE at various concentrations (0-200 µg/mL) markedly decreased AGS cell viability and increased apoptotic cell death dose and time dependently. CPE increased the levels of cleaved caspase-8, -7, -3, and poly (ADP-ribose) polymerase in a dose-dependent manner but not cleaved caspase-9. CPE exerted no effects on Bcl-2 and Bax levels. The level of X-linked inhibitor of apoptosis protein decreased within a narrow range following CPE treatment. The levels of Trail, DR4, and Fas-L increased dose-dependently in CPE-treated AGS cells. These results show that CPE decreases growth and induces apoptosis in AGS gastric cancer cells and that activation of the death receptor pathway contributes to CPE-induced apoptosis in AGS cells. In conclusion, CPE had more of an effect on gastric cancer cells than breast or prostate cancer cells, suggesting that chestnuts would have a positive effect against gastric cancer.

  5. Harmine combined with paclitaxel inhibits tumor proliferation and induces apoptosis through down-regulation of cyclooxygenase-2 expression in gastric cancer

    PubMed Central

    Yu, Xiao-Juan; Sun, Kun; Tang, Xiao-He; Zhou, Cun-Jin; Sun, Hui; Yan, Zhe; Fang, Ling; Wu, Hong-Wen; Xie, Yi-Kui; Gu, Bin

    2016-01-01

    Cyclooxygenase-2 (COX-2) serves an important role in the carcinogenesis and progression of gastric cancer. Harmine (HM) and paclitaxel (PTX) are reported as promising drug candidates for cancer therapy, but whether a synergistic anti-tumor effect of HM combined with PTX exists in human gastric cancer remains unknown. The present study evaluated the effects of HM and/or PTX on cell proliferation and apoptosis in a gastric cancer cell line, SGC-7901. HM and PTX inhibited cell proliferation in a dose-dependent manner. Both HM and PTX alone induced apoptosis in gastric cancer cells. The combination of HM and PTX exerted synergistic effects on proliferation inhibition and apoptosis induction in SGC-7901 cells, with down-regulation of COX-2, PCNA and Bcl-2 and up-regulation of Bax expression. The results indicated that combination chemotherapy using HM with PTX exerts an anti-tumor effect for treating gastric cancer. The combination of the two drugs inhibits gastric cancer development more effectively than each drug alone through down-regulation of COX-2 expression. PMID:27446381

  6. Dosimetric Analysis of Radiation-Induced Gastric Bleeding

    PubMed Central

    Feng, Mary; Normolle, Daniel; Pan, Charlie C.; Dawson, Laura A.; Amarnath, Sudha; Ensminger, William D.; Lawrence, Theodore S.; Ten Haken, Randall K.

    2012-01-01

    Purpose Radiation-induced gastric bleeding has been poorly understood. In this study, we describe dosimetric predictors for gastric bleeding after fractionated radiotherapy and compare several predictive models. Materials & Methods The records of 139 sequential patients treated with 3-dimensional conformal radiotherapy (3D-CRT) for intrahepatic malignancies between January 1999 and April 2002 were reviewed. Median follow-up was 7.4 months. Logistic regression and Lyman normal tissue complication probability (NTCP) models for the occurrence of ≥ grade 3 gastric bleed were fit to the data. The principle of maximum likelihood was used to estimate parameters for all models. Results Sixteen of 116 evaluable patients (14%) developed gastric bleeds, at a median time of 4.0 months (mean 6.5 months, range 2.1–28.3 months) following completion of RT. The median and mean of the maximum doses to the stomach were 61 and 63 Gy (range 46 Gy–86 Gy), respectively, after bio-correction to equivalent 2 Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis was most predictive of gastric bleed (AUROC=0.92). Best fit Lyman NTCP model parameters were n =0.10, and m =0.21, with TD50(normal) =56 Gy and TD50(cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD50 value for the cirrhosis patients points out their greater sensitivity. Conclusion This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding, and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation. PMID:22541965

  7. Dosimetric Analysis of Radiation-induced Gastric Bleeding

    SciTech Connect

    Feng, Mary; Normolle, Daniel; Pan, Charlie C.; Dawson, Laura A.; Amarnath, Sudha; Ensminger, William D.; Lawrence, Theodore S.; Ten Haken, Randall K.

    2012-09-01

    Purpose: Radiation-induced gastric bleeding has been poorly understood. In this study, we described dosimetric predictors for gastric bleeding after fractionated radiation therapy. Methods and Materials: The records of 139 sequential patients treated with 3-dimensional conformal radiation therapy (3D-CRT) for intrahepatic malignancies were reviewed. Median follow-up was 7.4 months. The parameters of a Lyman normal tissue complication probability (NTCP) model for the occurrence of {>=}grade 3 gastric bleed, adjusted for cirrhosis, were fitted to the data. The principle of maximum likelihood was used to estimate parameters for NTCP models. Results: Sixteen of 116 evaluable patients (14%) developed gastric bleeds at a median time of 4.0 months (mean, 6.5 months; range, 2.1-28.3 months) following completion of RT. The median and mean maximum doses to the stomach were 61 and 63 Gy (range, 46-86 Gy), respectively, after biocorrection of each part of the 3D dose distributions to equivalent 2-Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis predicted gastric bleed. Best-fit Lyman NTCP model parameters were n=0.10 and m=0.21 and with TD{sub 50} (normal) = 56 Gy and TD{sub 50} (cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD{sub 50} value for the cirrhosis patients points out their greater sensitivity. Conclusions: This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.

  8. The inhibitory effect of meadowsweet (Filipendula ulmaria) on radiation-induced carcinogenesis in rats.

    PubMed

    Bespalov, Vladimir G; Alexandrov, Valery A; Semenov, Alexandr L; Kovan'ko, Elena G; Ivanov, Sergey D; Vysochina, Galina I; Kostikova, Vera A; Baranenko, Denis A

    2017-04-01

    To examine the ability of the meadowsweet preparation to inhibit carcinogenesis induced by ionizing radiation in female rats. The chemical composition of meadowsweet (Filipendula ulmaria) raw material (ethanol and aqueous extracts of meadowsweet flowers) has been studied for the presence of flavonoids, tannins and catechins. Adult female LIO strain rats were subjected to a single whole body γ-irradiation at a dose of 4 Gy in animal experiments. One group of irradiated rats served as control while the other group, starting from the 10th day after irradiation and until the end of the experiment, was given meadowsweet as a decoction of the flowers instead of drinking water. The average daily intake of meadowsweet (dry raw material) was 1 g/kg body weight. Rats were observed for 16 months. The analyzed meadowsweet extracts showed a sufficiently high content of flavonoids and tannins. In irradiated rats after 16 months the overall incidence of tumors was 79.6% (in 82 of 103 rats), the incidence of malignant tumors was 43.7% and the overall tumor multiplicity was 1.48. Most tumors were localized in the mammary gland - 57.3%. In rats that received meadowsweet, the incidence of all malignant tumors and overall multiplicity of tumors were significantly decreased by 1.5 and 1.3 times, respectively. The greatest reduction of many parameters has been identified for breast tumors: the overall incidence was decreased by 1.5 (p = 0.0174) and the overall multiplicity and multiplicity of malignant tumors - by 1.6 (p = 0.0002) and 2.2 (p = 0.0383) times, respectively. Meadowsweet preparation showed inhibiting activity on radiation carcinogenesis.

  9. Chemopreventive activity of grape juice concentrate (G8000TM) on rat colon carcinogenesis induced by azoxymethane.

    PubMed

    Silva, Roseane Mendes; Campanholo, Vanessa Maria de Lima Pazine; Paiotti, Ana Paula Ribeiro; Artigiani Neto, Ricardo; Oshima, Celina Tizuko Fujiyama; Ribeiro, Daniel Araki; Forones, Nora Manoukian

    2015-11-01

    Colorectal cancer is the third most common cancer worldwide in both sexes, with similar geographic patterns between genders. This neoplasm has good prognosis if the disease is diagnosed at early stages. The aim of this study was to evaluate the effect of red grape juice on the expression of COX-2 and Ki-67 expression following colon carcinogenesis induced by azoxymethane (AOM). Thirty-five rats were randomly distributed into seven groups (n=5 per group): G1: SHAM or negative control received only saline; G2 (positive control): animals received 15 mg/kg AOM; G3: animals received 1% red grape juice 2 weeks before the administration of AOM; G4: animals received 2% red grape juice 2 weeks before the administration of AOM; G5: animals received 1% red grape juice 4 weeks after the last administration of AOM; G6: animals received 2% red grape juice 4 weeks after the last administration of AOM; G7: animals received only 2% red grape juice. COX-2 mRNA expression was reduced in animals treated with 1% red grape juice before AOM induction or 2% red grape juice after AOM induction. COX-2 immunoexpression was also reduced to groups treated with red grape juice at 1% before and after AOM induction or 2% red grape juice after AOM induction. Decreased immunoexpression of Ki-67 positive cells was observed in animals treated with 1% grape juice before AOM-treated animals. Taken together, grape juice concentrate is able to exert some chemopreventive activity on rat colon carcinogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Modifying effects of Terminalia catappa on azoxymethane-induced colon carcinogenesis in male F344 rats.

    PubMed

    Morioka, T; Suzui, M; Nabandith, V; Inamine, M; Aniya, Y; Nakayama, T; Ichiba, T; Yoshimi, N

    2005-04-01

    The modifying effects of dietary administration of an herb, Terminalia catappa (TC), were investigated on rat colon carcinogenesis induced by a carcinogen azoxymethane (AOM). The number of aberrant crypt foci (ACF) and beta-catenin accumulated crypts (BCACs) in the colon, and proliferating cell nuclear antigen (PCNA) labelling index in the colonic epithelium were examined in a total of 36 male F344 rats. All animals were randomly divided into five experimental groups (4-10 rats in each group). At 6 weeks of age, rats in groups 1, 2 and 3 were given s.c. injections of AOM once a week for 2 weeks at a concentration of 20 mg/kg body weight. One week before the first injection of AOM, rats in groups 2 and 3 were fed a diet containing 0.02 and 0.1% TC, respectively, throughout the experiment. Rats in group 4 were fed a diet containing 0.1% TC. Rats in group 5 were served as untreated controls. All animals were sacrificed at the experimental week 5 after the start of the experiment. Oral administration of TC at both doses significantly decreased the numbers of both ACF/colon/rat (P<0.05 for 0.02% TC, P<0.005 for 0.1% TC) and BCAC/cm/rat (P<0.05 for both 0.02 and 0.1% TC), when compared with the control group (group 1). Colonic PCNA labelling index in groups 2 and 3 was also significantly lower than that in group 1 (P<0.001 for 0.02% TC, P<0.005 for 0.1% TC). These results suggest that TC has a potent short-term chemopreventive effect on biomarkers of colon carcinogenesis and this effect may be associated with the inhibition of the development of ACF and BCACs.

  11. Formation of acrolein-derived 2'-deoxyadenosine adduct in an iron-induced carcinogenesis model.

    PubMed

    Kawai, Yoshichika; Furuhata, Atsunori; Toyokuni, Shinya; Aratani, Yasuaki; Uchida, Koji

    2003-12-12

    Acrolein is a representative carcinogenic aldehyde found ubiquitously in the environment and formed endogenously through oxidation reactions, such as lipid peroxidation and myeloperoxidase-catalyzed amino acid oxidation. It shows facile reactivity toward DNA to form an exocyclic DNA adduct. To verify the formation of acrolein-derived DNA adduct under oxidative stress in vivo, we raised a novel monoclonal antibody (mAb21) against the acrolein-modified DNA and found that the antibody most significantly recognized an acrolein-modified 2' -deoxyadenosine. On the basis of chemical and spectroscopic evidence, the major antigenic product of mAb21 was the 1,N6-propano-2' -deoxyadenosine adduct. The exposure of rat liver epithelial RL34 cells to acrolein resulted in a significant accumulation of the acrolein-2' -deoxyadenosine adduct in the nuclei. Formation of this adduct under oxidative stress in vivo was immunohistochemically examined in rats exposed to ferric nitrilotriacetate, a carcinogenic iron chelate that specifically induces oxidative stress in the kidneys of rodents. It was observed that the acrolein-2' -deoxyadenosine adduct was formed in the nuclei of the proximal tubular cells, the target cells of this carcinogenesis model. The same cells were stained with a monoclonal antibody 5F6 that recognizes an acrolein-lysine adduct, by which cytosolic accumulation of acrolein-modified proteins appeared. Similar results were also obtained from myeloperoxidase knockout mice exposed to the iron complex, suggesting that the myeloperoxidase-catalyzed oxidation system might not be essential for the generation of acrolein in this experimental animal carcinogenesis model. The data obtained in this study suggest that the formation of a carcinogenic aldehyde through lipid peroxidation may be causally involved in the pathophysiological effects associated with oxidative stress.

  12. Chemopreventive effect of Cynodon dactylon (L.) Pers. extract against DMH-induced colon carcinogenesis in experimental animals.

    PubMed

    Albert-Baskar, Arul; Ignacimuthu, Savarimuthu

    2010-07-01

    The present study was aimed at evaluating the chemopreventive property of Cynodon dactylon. The antioxidant, antiproliferative and apoptotic potentials of the plant were investigated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay, nitric oxide radical scavenging activity (NO(-)) and MTT assay on four cancer cell lines (COLO 320 DM, MCH-7, AGS, A549) and a normal cell line (VERO). In vivo chemopreventive property of the plant extract was studied in DMH-induced colon carcinogenesis. The methanolic extract of C. dactylon was found to be antiproliferative and antioxidative at lower concentrations and induced apoptotic cell death in COLO 320 DM cells. Treatment with methanolic extract of C. dactylon increased the levels of antioxidant enzymes and reduced the number of dysplastic crypts in DMH-induced colon of albino rats. The present investigation revealed the anticancer potential of methanolic extract of C. dactylon in COLO 320 DM cells and experimentally induced colon carcinogenesis in rats.

  13. Curcumin-induced histone acetylation inhibition improves stress-induced gastric ulcer disease in rats.

    PubMed

    He, Ping; Zhou, Renmin; Hu, Guorui; Liu, Zhifeng; Jin, Yu; Yang, Guang; Li, Mei; Lin, Qian

    2015-03-01

    Curcumin is known to possess anti‑inflammatory properties. Despite the fact that curcumin is known to be a strong inhibitor of H+, K+‑ATPase activity, the mechanism underlying the curcumin‑induced inhibition of the transcription of the H+, K+‑ATPase α subunit in gastric mucosal parietal cells remains unclear. The present study investigated the possible mechanism by which curcumin inhibits stomach H+, K+‑ATPase activity during the acute phase of gastric ulcer disease. A rat model of stress‑induced gastric ulcers was produced, in which the anti‑ulcer effects of curcumin were examined. Curcumin‑induced inhibition of the H+, K+‑ATPase promoter via histone acetylation, was verified using a chromatin immunoprecipitation assay. The results showed that curcumin improved stress‑induced gastric ulcer disease in rats, as demonstrated by increased pH values and reduced gastric mucosal hemorrhage and ulcer index. These effects were accompanied by a significant reduction in the level of histone H3 acetylation at the site of the H+, K+‑ATPase promoter and in the expression of the gastric H+,K+‑ATPase α subunit gene and protein. In conclusion, curcumin downregulated the acetylation of histone H3 at the site of the H+, K+‑ATPase promoter gene, thereby inhibiting the transcription and expression of the H+, K+‑ATPase gene. Curcumin was shown to have a preventive and therapeutic effect in gastric ulcer disease.

  14. ERK1/2 inhibition enhances apoptosis induced by JAK2 silencing in human gastric cancer SGC7901 cells.

    PubMed

    Qian, Cuijuan; Yao, Jun; Wang, Jiji; Wang, Lan; Xue, Meng; Zhou, Tianhua; Liu, Weili; Si, Jianmin

    2014-02-01

    Recent studies suggest JAK2 signaling may be a therapeutic target for treatment of gastric cancer (GC). However, the exact roles of JAK2 in gastric carcinogenesis are not very clear. Here, we have targeted JAK2 to be silenced by shRNA and investigated the biological functions and related mechanisms of JAK2 in GC cell SGC7901. In this study, JAK2 is commonly highly expressed in GC tissues as compared to their adjacent normal tissues (n = 75, p < 0.01). Specific down-regulation of JAK2 suppressed cell proliferation and colony-forming units, induced G2/M arrest in SGC7901 cells, but had no significant effect on cell apoptosis in vitro or tumor growth inhibition in vivo. Interestingly, JAK2 silencing-induced activation of ERK1/2, and inactivation of ERK1/2 using the specific ERK inhibitor PD98059 markedly enhanced JAK2 shRNA-induced cell proliferation inhibition, cell cycle arrest and apoptosis. Ultimately, combination of PD98059 and JAK2 shRNA significantly inhibited tumor growth in nude mice. Our results implicate JAK2 silencing-induced cell proliferation inhibition, cell cycle arrest, and ERK1/2 inhibition could enhance apoptosis induced by JAK2 silencing in SGC7901 cells.

  15. In vitro and in vivo studies on antitumor effects of gossypol on human stomach adenocarcinoma (AGS) cell line and MNNG induced experimental gastric cancer

    SciTech Connect

    Gunassekaran, G.R.; Kalpana Deepa Priya, D.; Gayathri, R.; Sakthisekaran, D.

    2011-08-12

    Highlights: {yields} Gossypol is a well known polyphenolic compound used for anticancer studies but we are the first to report that gossypol has antitumor effect on MNNG induced gastric cancer in experimental animal models. {yields} Our study shows that gossypol inhibits the proliferation of AGS (human gastric adenocarcinoma) cell line. {yields} In animal models, gossypol extends the survival of cancer bearing animals and also protects the cells from carcinogenic effect. {yields} So we suggest that gossypol would be a potential chemotherapeutic and chemopreventive agent for gastric cancer. -- Abstract: The present study has evaluated the chemopreventive effects of gossypol on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced gastric carcinogenesis and on human gastric adenocarcinoma (AGS) cell line. Gossypol, C{sub 30}H{sub 30}O{sub 8}, is a polyphenolic compound that has anti proliferative effect and induces apoptosis in various cancer cells. The aim of this work was to delineate in vivo and in vitro anti-initiating mechanisms of orally administered gossypol in target (stomach) tissues and in human gastric adenocarcinoma (AGS) cell line. In vitro results prove that gossypol has potent cytotoxic effect and inhibit the proliferation of adenocarcinoma (AGS) cell line. In vivo results prove gossypol to be successful in prolonging the survival of MNNG induced cancer bearing animals and in delaying the onset of tumor in animals administrated with gossypol and MNNG simultaneously. Examination of the target (stomach) tissues in sacrificed experimental animals shows that administration of gossypol significantly reduces the level of tumor marker enzyme (carcino embryonic antigen) and pepsin. The level of Nucleic acid contents (DNA and RNA) significantly reduces, and the membrane damage of glycoprotein subsides, in the target tissues of cancer bearing animals, with the administration of gossypol. These data suggest that gossypol may create a beneficial effect in patients

  16. Mechanisms of epigenetic silencing of the Rassf1a gene during estrogen-induced breast carcinogenesis in ACI rats.

    PubMed

    Starlard-Davenport, Athena; Tryndyak, Volodymyr P; James, Smitha R; Karpf, Adam R; Latendresse, John R; Beland, Frederick A; Pogribny, Igor P

    2010-03-01

    Breast cancer, the most common malignancy in women, emerges through a multistep process, encompassing the progressive sequential evolution of morphologically distinct stages from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma and metastasis. The success of treatment of breast cancer could be greatly improved by the detection at early stages of cancer. In the present study, we investigated the underlying molecular mechanisms involved in breast carcinogenesis in Augustus and Copenhagen-Irish female rats, a cross between the ACI strains, induced by continuous exposure to 17beta-estradiol. The results of our study demonstrate that early stages of estrogen-induced breast carcinogenesis are characterized by altered global DNA methylation, aberrant expression of proteins responsible for the proper maintenance of DNA methylation pattern and epigenetic silencing of the critical Rassf1a (Ras-association domain family 1, isoform A) tumor suppressor gene. Interestingly, transcriptional repression of the Rassf1a gene in mammary glands during early stages of breast carcinogenesis was associated with an increase in trimethylation of histones H3 lysine 9 and H3 lysine 27 and de novo CpG island methylation and at the Rassf1a promoter and first exon. In conclusion, we demonstrate that epigenetic alterations precede formation of preneoplastic lesions indicating the significance of epigenetic events in induction of oncogenic pathways in early stages of carcinogenesis.

  17. Soluble Epoxide Hydrolase Deficiency Inhibits Dextran Sulfate Sodium-induced Colitis and Carcinogenesis in Mice

    PubMed Central

    DONG, HUA; LIAO, JIE; HAMMOCK, BRUCE D.; YANG, GUANG-YU

    2014-01-01

    Soluble epoxide hydrolase (sEH) hydrolyses/inactivates anti-inflammatory epoxyeicosatrienoic acids (EETs) to their corresponding diols, and targeting sEH leads to strong anti-inflammatory effects. In the present study, using a tissue microarray and immunohistochemical approach, a significant increase of sEH expression was identified in ulcerative colitis (UC)-associated dysplasia and adenocarcinoma. The effects of deficiency in the sEH gene were determined on dextran sulfate sodium (DSS) colitis-induced carcinogenesis. The effects of EETs on lipopolysaccharide (LPS)-activated macrophages were analyzed in vitro. With extensive histopathological and immunohistochemical analyses, compared to wild-type mice, sEH−/− mice exhibited a significant decrease in tumor incidence (13/20 vs. 6/19, p<0.05) and a markedly reduced average tumor size (59.62±20.91 mm3 vs. 22.42±11.22 mm3), and a significant number of pre-cancerous dysplasia (3±1.18 vs. 2±0.83, p<0.01). The inflammatory activity, as measured by the extent/proportion of erosion/ulceration/dense lymphoplasmacytosis (called active colitis index) in the colon, was significantly lower in sEH−/− mice (44.7%±24.9% vs. 20.2%±16.2%, p<0.01). The quantitative polymerase chain reaction (qPCR) assays demonstrated significantly low levels of cytokines/chemokines including monocyte chemoattractant protein (MCP-1), inducible nitric oxide synthase (iNOS), vasopressin-activated calcium-mobilizing (VCAM-1), interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). In vitro, LPS-activated macrophages treated with 14,15-EET showed a significant reduction of LPS-triggered IL-1β and TNF-α expression. Eicosanoic acid metabolic profiling revealed a significant increase of the ratios of EETs/dihydroeicosatrienoic acids (DHETs) and epoxyoctadecennoic acid/dihydroxyoctadecenoic acid (EpOMEs/DiHOMEs). These results indicate that sEH plays an important role in the development of colitis and in inducing carcinogenesis

  18. Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells.

    PubMed

    Liszt, Kathrin Ingrid; Ley, Jakob Peter; Lieder, Barbara; Behrens, Maik; Stöger, Verena; Reiner, Angelika; Hochkogler, Christina Maria; Köck, Elke; Marchiori, Alessandro; Hans, Joachim; Widder, Sabine; Krammer, Gerhard; Sanger, Gareth John; Somoza, Mark Manuel; Meyerhof, Wolfgang; Somoza, Veronika

    2017-07-25

    Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine's bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH.

  19. Caffeine induces gastric acid secretion via bitter taste signaling in gastric parietal cells

    PubMed Central

    Liszt, Kathrin Ingrid; Ley, Jakob Peter; Lieder, Barbara; Behrens, Maik; Stöger, Verena; Reiner, Angelika; Hochkogler, Christina Maria; Köck, Elke; Marchiori, Alessandro; Hans, Joachim; Widder, Sabine; Krammer, Gerhard; Sanger, Gareth John; Somoza, Mark Manuel; Meyerhof, Wolfgang

    2017-01-01

    Caffeine, generally known as a stimulant of gastric acid secretion (GAS), is a bitter-tasting compound that activates several taste type 2 bitter receptors (TAS2Rs). TAS2Rs are expressed in the mouth and in several extraoral sites, e.g., in the gastrointestinal tract, in which their functional role still needs to be clarified. We hypothesized that caffeine evokes effects on GAS by activation of oral and gastric TAS2Rs and demonstrate that caffeine, when administered encapsulated, stimulates GAS, whereas oral administration of a caffeine solution delays GAS in healthy human subjects. Correlation analysis of data obtained from ingestion of the caffeine solution revealed an association between the magnitude of the GAS response and the perceived bitterness, suggesting a functional role of oral TAS2Rs in GAS. Expression of TAS2Rs, including cognate TAS2Rs for caffeine, was shown in human gastric epithelial cells of the corpus/fundus and in HGT-1 cells, a model for the study of GAS. In HGT-1 cells, various bitter compounds as well as caffeine stimulated proton secretion, whereby the caffeine-evoked effect was (i) shown to depend on one of its cognate receptor, TAS2R43, and adenylyl cyclase; and (ii) reduced by homoeriodictyol (HED), a known inhibitor of caffeine’s bitter taste. This inhibitory effect of HED on caffeine-induced GAS was verified in healthy human subjects. These findings (i) demonstrate that bitter taste receptors in the stomach and the oral cavity are involved in the regulation of GAS and (ii) suggest that bitter tastants and bitter-masking compounds could be potentially useful therapeutics to regulate gastric pH. PMID:28696284

  20. Iron overload as a major targetable pathogenesis of asbestos-induced mesothelial carcinogenesis.

    PubMed

    Toyokuni, Shinya

    2014-01-01

    Few people expected that asbestos, a fibrous mineral, would be carcinogenic to humans. In fact, asbestos is a definite carcinogen in humans, causing a rare but aggressive cancer called malignant mesothelioma (MM). Mesothelial cells line the three somatic cavities and thus do not face the outer surface, but reduce the friction among numerous moving organs. MM has several characteristics: extremely long incubation period of 30-40 years after asbestos exposure, difficulty in clinical diagnosis at an early stage, and poor prognosis even under the current multimodal therapies. In Japan, 'Kubota shock' attracted considerable social attention in 2005 for asbestos-induced mesothelioma and, thereafter, the government enacted a law to provide the people suffering from MM a financial allowance. Several lines of recent evidence suggest that the major pathology associated with asbestos-induced MM is local iron overload, associated with asbestos exposure. Preclinical studies to prevent MM after asbestos exposure with iron reduction are in progress. In addition, novel target genes in mesothelial carcinogenesis have been discovered with recently recognized mesothelioma-prone families. Development of an effective preventive strategy is eagerly anticipated because of the long incubation period for MM.

  1. Dietary Emulsifier-Induced Low-Grade Inflammation Promotes Colon Carcinogenesis.

    PubMed

    Viennois, Emilie; Merlin, Didier; Gewirtz, Andrew T; Chassaing, Benoit

    2017-01-01

    The increased risks conferred by inflammatory bowel disease (IBD) to the development of colorectal cancer gave rise to the term "colitis-associated cancer" and the concept that inflammation promotes colon tumorigenesis. A condition more common than IBD is low-grade inflammation, which correlates with altered gut microbiota composition and metabolic syndrome, both present in many cases of colorectal cancer. Recent findings suggest that low-grade inflammation in the intestine is promoted by consumption of dietary emulsifiers, a ubiquitous component of processed foods, which alter the composition of gut microbiota. Here, we demonstrate in a preclinical model of colitis-induced colorectal cancer that regular consumption of dietary emulsifiers, carboxymethylcellulose or polysorbate-80, exacerbated tumor development. Enhanced tumor development was associated with an altered microbiota metagenome characterized by elevated levels of lipopolysaccharide and flagellin. We found that emulsifier-induced alterations in the microbiome were necessary and sufficient to drive alterations in major proliferation and apoptosis signaling pathways thought to govern tumor development. Overall, our findings support the concept that perturbations in host-microbiota interactions that cause low-grade gut inflammation can promote colon carcinogenesis. Cancer Res; 77(1); 27-40. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis

    PubMed Central

    Deshmukh, Jayesh; Pofahl, Ruth; Haase, Ingo

    2017-01-01

    Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways. PMID:28277539

  3. Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis.

    PubMed

    Deshmukh, Jayesh; Pofahl, Ruth; Haase, Ingo

    2017-03-09

    Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways.

  4. Helicobacter pylori-induced apoptosis in pathogenesis of gastric carcinoma.

    PubMed

    Tiwari, Shridhar; Ghoshal, Ujjala; Ghoshal, Uday C; Dhingra, Sadhna; Pandey, Rakesh; Singh, Manisha; Ayyagari, Archana; Naik, Sita

    2005-01-01

    Despite a possible role of Helicobacter pylori in gastric carcinoma (GC), its pathogenesis is not clear. There is scanty data on apoptosis in GC in relation to H. pylori and CagA antibody. Therefore, we studied gastric epithelial apoptosis in GC and non-ulcer dyspepsia (NUD) with or without H. pylori infection, and the degree of apoptosis in relation to CagA antibody status. 20 patients each with GC and NUD were investigated for H. pylori using rapid urease test (RUT), IgG anti-H. pylori and anti-CagA antibodies, histology of endoscopically normal-looking mucosa for H. pylori, intestinal metaplasia (IM), and apoptosis using TUNEL assay. Positivity to one tissue-based (RUT or histology) and one serology based (anti-H. pylori or CagA IgG) test was taken as diagnostic of active H. pylori infection, and negative result in both tissue-based tests suggested its absence. Patients with GC more often had anti-H. pylori IgG (16 of 20 vs. 8 of 20; p=0.02) and a trend towards higher apoptotic index (AI) (48.6 [19.2 to 71.7] vs. 41.4 [11.7 to 63.6]; p=0.06) than NUD. AI was higher in GC (66.7 [57.5 to 71.7] vs. 32.6 [19.2 to 39.8]; p<0.0001) and NUD (58.6 [50.7 to 63.6] vs. 24.4 [11.7 to 32.2]; p<0.0001) infected with H. pylori than in those without infection. AI was also higher in GC than in NUD with H. pylori infection (66.7 [57.5 to 71.7] vs. 58.6 [50.7 to 63.6]; p=0.01). Four of the 20 patients with GC and none with NUD had IM (p=ns). There was no difference in AI in relation to CagA antibody. AI positively correlated with patients' age in presence of H. pylori infection (correlation coefficient=0.5, p=0.03) but not in its absence. Exaggerated apoptosis may play a role in H. pylori-mediated gastric diseases including carcinogenesis. AI increases with aging in patients infected with H. pylori.

  5. The Role of TLR2, TLR4 and CD14 Genetic Polymorphisms in Gastric Carcinogenesis: A Case-Control Study and Meta-Analysis

    PubMed Central

    Castaño-Rodríguez, Natalia; Kaakoush, Nadeem O.; Goh, Khean-Lee; Fock, Kwong Ming; Mitchell, Hazel M.

    2013-01-01

    Background In addition to Helicobacter pylori infection, host genetic factors contribute to gastric cancer (GC). Recognition of H. pylori is known to involve Toll-like receptors (TLR), which subsequently leads to activation of NF-κB. Thus, the overall aim of this study was to estimate for the first time the pooled effect size of polymorphisms in TLR2, TLR4 and CD14 on GC development through a meta-analysis. Methods A case-control study comprising 284 ethnic Chinese individuals (70 non-cardia GC cases and 214 functional dyspepsia controls) was conducted for the genotyping of TLR2 -196 to -174del, CD14 -260 C/T and TLR4 rs11536889 using PCR, RT-PCR and mass spectrometry. Case-control studies of TLR2, TLR4 and CD14 polymorphisms and GC were searched up to June 2012. Pooled odds ratios and 95% confidence intervals were obtained by means of the random effects model. Results In our ethnic Chinese case-control study, the TLR4 rs11536889 C allele increased the risk of GC (OR: 1.89, 95%CI: 1.23–2.92) while the CD14 -260 T allele was protective (OR: 0.62, 95%CI: 0.42–0.91). TLR2 -196 to -174 increased the risk of GC only in H. pylori-infected individuals (OR: 3.10, 95%CI: 1.27–7.60). In the meta-analysis, TLR4 Asp299Gly showed borderline results in the general analysis (pooled OR: 1.58, 95%CI: 0.98–2.60), nevertheless, stratified analysis by ethnicity showed that the mutant allele was a definitive risk factor for GC in Western populations (pooled OR: 1.87, 95%CI: 1.31–2.65). There was a potential association between the TLR2 -196 to -174 deletion allele and GC in Japanese (pooled OR: 1.18, 95%CI: 0.96–1.45). TLR4 Thr399Ile did not provide significant results. Conclusions TLR4 rs11536889 and CD14 -260 C/T are associated with non-cardia GC in Chinese. Based on our meta-analysis, the TLR signalling pathway is involved in gastric carcinogenesis, TLR4 Asp299Gly and TLR2 -196 to -174del showing associations with GC in an ethnic-specific manner. PMID:23565226

  6. Preventive effect of teprenone on stress-induced gastric mucosal lesions and its relation to gastric mucosal constitutive nitric oxide synthase activity.

    PubMed

    Nishida, K; Ohta, Y; Ishiguro, I

    1999-04-01

    Recently, we demonstrated that teprenone, an anti-ulcer agent, exerts protective and preventive actions against water immersion restraint (WIR) stress-induced gastric mucosal lesions in rats both by inhibiting neutrophil infiltration into the gastric mucosal tissue and by preserving gastric mucus synthesis and secretion. In rats with WIR stress we have also found a decrease in gastric mucosal constitutive nitric oxide synthase (cNOS) activity and a drastic increase in gastric mucosal inducible nitric oxide synthase (iNOS) activity. The decrease in gastric mucosal cNOS activity is closely related to an increase in neutrophil infiltration into the gastric mucosa and a decrease in the level of gastric mucus. In this study of WIR-stressed rats, therefore, we examined whether the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats are related to the change in gastric mucosal cNOS activity during the development of gastric mucosal lesions. Pre-administration of teprenone (200 mg kg-1) prevented the decrease in gastric mucosal cNOS activity with attenuations of neutrophil infiltration into gastric mucosal tissues and decreased levels of gastric mucosal hexosamine, an index of gastric mucin, and adherent mucus in rats with 3 or 6 h of WIR stress. These preventive effects of teprenone on the gastric mucosal neutrophil infiltration and the decrease in gastric mucus levels in rats with WIR stress were completely reversed with inhibition of gastric mucosal cNOS activity by co-administration of NG-monomethyl L-arginine (L-NMMA), a non-selective NOS inhibitor. These results suggest that the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats with WIR stress are closely related to the maintenance of cNOS activity in the gastric mucosal tissue. Copyright 1999 The Italian Pharmacological Society.

  7. Gastric hypersensitivity induced by oesophageal acid infusion in healthy volunteers.

    PubMed

    van den Elzen, B D J; Tytgat, G N J; Boeckxstaens, G E E

    2009-02-01

    Distal oesophageal acid exposure has been shown to increase visceral sensitivity of the proximal oesophagus via central sensitization. Here we evaluated whether acidification of the distal oesophagus also affects the sensorimotor function of the proximal stomach. A gastric barostat study combined with a 30-min acid (HCl 0.15 mol L(-1)) or saline infusion in the distal oesophagus was performed in 18 healthy volunteers. Gastric and cutaneous sensitivity was assessed before and up to 2 h after the start of infusion. Directly after acid infusion, but not after saline, the threshold for discomfort decreased (-6.4 +/- 1.7 vs 0.4 +/- 0.4 mmHg; P = 0.028) and distension-induced symptoms increased significantly compared with the baseline (122 +/- 49% vs -3 +/- 9%). Cutaneous sensitivity remained unaffected by acid infusion. In contrast, when the infused liquid was aspirated 3 cm more distally, at the level of the lower oesophageal sphincter, the effect of acid infusion on gastric sensitivity was abolished and the increase in distension-induced symptoms was reduced (61 +/- 24%). Distal oesophageal acid infusion induces visceral hypersensitivity without affecting somatic sensitivity arguing against a similar mechanism of central sensitization as observed in non-cardiac chest pain. As reduction of the acid load to the stomach prevented this effect, our findings indicate that either gastric and/or duodenal acidification is involved. It should be emphasized though that aspiration from distal oesophagus may have attenuated the effect by reducing the acid-exposed area or by reducing the contact time.

  8. DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis.

    PubMed

    Fahrer, Jörg; Frisch, Janina; Nagel, Georg; Kraus, Alexander; Dörsam, Bastian; Thomas, Adam D; Reißig, Sonja; Waisman, Ari; Kaina, Bernd

    2015-10-01

    Epidemiological studies indicate that N-nitroso compounds (NOC) are causally linked to colorectal cancer (CRC). NOC induce DNA alkylations, including O (6)-methylguanine (O (6)-MeG) and N-methylated purines, which are repaired by O (6)-MeG-DNA methyltransferase (MGMT) and N-alkyladenine-DNA glycosylase (AAG)-initiated base excision repair, respectively. In view of recent evidence of nonlinear mutagenicity for NOC-like compounds, the question arises as to the existence of threshold doses in CRC formation. Here, we set out to determine the impact of DNA repair on the dose-response of alkylation-induced CRC. DNA repair proficient (WT) and deficient (Mgmt (-/-), Aag (-/-) and Mgmt (-/-)/Aag (-/-)) mice were treated with azoxymethane (AOM) and dextran sodium sulfate to trigger CRC. Tumors were quantified by non-invasive mini-endoscopy. A non-linear increase in CRC formation was observed in WT and Aag (-/-) mice. In contrast, a linear dose-dependent increase in tumor frequency was found in Mgmt (-/-) and Mgmt (-/-)/Aag (-/-) mice. The data were corroborated by hockey stick modeling, yielding similar carcinogenic thresholds for WT and Aag (-/-) and no threshold for MGMT lacking mice. O (6)-MeG levels and depletion of MGMT correlated well with the observed dose-response in CRC formation. AOM induced dose-dependently DNA double-strand breaks in colon crypts including Lgr5-positive colon stem cells, which coincided with ATR-Chk1-p53 signaling. Intriguingly, Mgmt (-/-) mice displayed significantly enhanced levels of γ-H2AX, suggesting the usefulness of γ-H2AX as an early genotoxicity marker in the colorectum. This study demonstrates for the first time a non-linear dose-response for alkylation-induced colorectal carcinogenesis and reveals DNA repair by MGMT, but not AAG, as a key node in determining a carcinogenic threshold.

  9. Beef meat promotion of dimethylhydrazine-induced colorectal carcinogenesis biomarkers is suppressed by dietary calcium.

    PubMed

    Pierre, Fabrice; Santarelli, Raphaëlle; Taché, Sylviane; Guéraud, Françoise; Corpet, Denis E

    2008-05-01

    Red meat consumption is associated with increased risk of colorectal cancer. We have previously shown that haemin, Hb and red meat promote carcinogen-induced preneoplastic lesions: aberrant crypt foci (ACF) and mucin-depleted foci (MDF) in rats. We have also shown that dietary Ca, antioxidant mix and olive oil inhibit haemin-induced ACF promotion, and normalize faecal lipoperoxides and cytotoxicity. Here we tested if these strategies are effective also against red meat promotion in dimethylhydrazine-induced rats. Three diets with 60 % beef meat were supplemented with calcium phosphate (31 g/kg), antioxidant agents (rutin and butylated hydroxyanisole, 0.05 % each) and olive oil (5 %). ACF, MDF, faecal water cytotoxicity, thiobarbituric acid reactive substances (TBARS) and urinary 1,4-dihydroxynonane mercapturic acid (DHN-MA) were measured. Beef meat diet increased the number of ACF (+30 %) and MDF (+100 %) (P < 0.001), which confirms our previous findings. Promotion was associated with increased faecal water TBARs ( x 4) and cytotoxicity ( x 2), and urinary DHN-MA excretion ( x 15). Ca fully inhibited beef meat-induced ACF and MDF promotion, and normalized faecal TBARS and cytotoxicity, but did not reduce urinary DHN-MA. Unexpectedly, high-calcium control diet-fed rats had more MDF and ACF in the colon than low-Ca control diet-fed rats. Antioxidant mix and olive oil did not normalize beef meat promotion nor biochemical factors. The results confirm that haem causes promotion of colon carcinogenesis by red meat. They suggest that Ca can reduce colorectal cancer risk in meat-eaters. The results support the concept that toxicity associated with the excess of a useful nutrient may be prevented by another nutrient.

  10. YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis process.

    PubMed

    Leal, Mariana Ferreira; Ribeiro, Helem Ferreira; Rey, Juan Antonio; Pinto, Giovanny Rebouças; Smith, Marília Cardoso; Moreira-Nunes, Caroline Aquino; Assumpção, Paulo Pimentel; Lamarão, Leticia Martins; Calcagno, Danielle Queiroz; Montenegro, Raquel Carvalho; Burbano, Rommel Rodriguez

    2016-12-20

    We previously observed reduced YWHAE (14-3-3ε) protein expression in a small set of gastric cancer samples. YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene. The understanding of YWHAE role and its targets is important for the better knowledge of gastric carcinogenesis. Thus, we aimed to evaluate the relationship among YWHAE, CDC25B, and MYC in vitro and in vivo. For this, we analyzed the YWHAE, CDC25B, and MYC expression in YWHA-silenced, CDC25B-silenced, and MYC-silenced gastric cancer cell lines, as well as in gastric cancer and non-neoplastic gastric samples. In gastric cancer cell lines, YWHAE was able to inhibit the cell proliferation, invasion and migration through the reduction of MYC and CDC25B expression. Conversely, MYC induced the cell proliferation, invasion and migration through the induction of CDC25B and the reduction of YWHAE. Most of the tumors presented reduced YWHAE and increased CDC25B expression, which seems to be important for tumor development. Increased MYC expression was a common finding in gastric cancer and has a role in poor prognosis. In the tumor initiation, the opposite role of YWHAE and CDC25B in gastric carcinogenesis seems to be independent of MYC expression. However, the inversely correlation between YWHAE and MYC expression seems to be important for gastric cancer cells invasion and migration. The interaction between YWHAE and MYC and the activation of the pathways related to this interaction play a role in the metastasis process.

  11. YWHAE silencing induces cell proliferation, invasion and migration through the up-regulation of CDC25B and MYC in gastric cancer cells: new insights about YWHAE role in the tumor development and metastasis process

    PubMed Central

    Rey, Juan Antonio; Pinto, Giovanny Rebouças; Smith, Marília Cardoso; Moreira-Nunes, Caroline Aquino; Assumpção, Paulo Pimentel; Lamarão, Leticia Martins; Calcagno, Danielle Queiroz; Montenegro, Raquel Carvalho; Burbano, Rommel Rodriguez

    2016-01-01

    We previously observed reduced YWHAE (14-3-3ε) protein expression in a small set of gastric cancer samples. YWHAE may act as a negative regulator of the cyclin CDC25B, which is a transcriptional target of MYC oncogene. The understanding of YWHAE role and its targets is important for the better knowledge of gastric carcinogenesis. Thus, we aimed to evaluate the relationship among YWHAE, CDC25B, and MYC in vitro and in vivo. For this, we analyzed the YWHAE, CDC25B, and MYC expression in YWHA-silenced, CDC25B-silenced, and MYC-silenced gastric cancer cell lines, as well as in gastric cancer and non-neoplastic gastric samples. In gastric cancer cell lines, YWHAE was able to inhibit the cell proliferation, invasion and migration through the reduction of MYC and CDC25B expression. Conversely, MYC induced the cell proliferation, invasion and migration through the induction of CDC25B and the reduction of YWHAE. Most of the tumors presented reduced YWHAE and increased CDC25B expression, which seems to be important for tumor development. Increased MYC expression was a common finding in gastric cancer and has a role in poor prognosis. In the tumor initiation, the opposite role of YWHAE and CDC25B in gastric carcinogenesis seems to be independent of MYC expression. However, the inversely correlation between YWHAE and MYC expression seems to be important for gastric cancer cells invasion and migration. The interaction between YWHAE and MYC and the activation of the pathways related to this interaction play a role in the metastasis process. PMID:27863420

  12. Aripiprazole an atypical antipsychotic protects against ethanol induced gastric ulcers in rats

    PubMed Central

    Asmari, Abdulrahman Al; Arshaduddin, Mohammed; Elfaki, Ibrahim; Kadasah, Saeed; Robayan, Abdulrahman Al; Asmary, Saeed Al

    2014-01-01

    The present investigation was undertaken, to study the gastro-protective potential of aripiprazole (ARI) an atypical antipsychotic drug in ethanol induced gastric ulcers in rats. ARI (10, 30, 100 mg/kg) was tested for gastric secretion and antiulcer activity in different groups of male Sprague Dawley rats. Gastric secretion and acidity studies were performed in pylorus ligated rats while indices of gastric ulcers were measured in ethanol (1 ml-100%) induced gastric ulcers. Histological changes and the levels of gastric wall mucus, malondialdehyde (MDA), non-protein sulfhydryls (NP-SH), myeloperoxidase (MPO), and serotonin were used to assess ethanol induced gastric mucosal injuries. Exposure of rats to ethanol resulted in gastric mucosal injury and a high index of ulcer. Pretreatment with ARI significantly (P < 0.001), reduced the gastric lesions induced by ethanol and also resulted in a significant decrease in the gastric secretion, and total acidity in pylorus ligated rats. ARI also significantly attenuated the ethanol induced reduction in the levels of gastric wall mucus, and NP-SH (P < 0.001). The histological changes and the increased MDA and MPO activity were also significantly (P < 0.001) inhibited by ARI. Ethanol induced depletion in the levels of serotonin in the gastric tissue were also significantly restored by pretreatment with ARI (p < 0.001). ARI showed significant antiulcer and gastroprotective activity against ethanol induced gastric ulcers. The gastroprotective effects of ARI may be due to its anti-secretory, antioxidant and anti-inflammatory action and also due to the restoration of the depleted gastric serotonin levels. PMID:25232384

  13. Multi-step lung carcinogenesis model induced by oral administration of N-nitrosobis(2-hydroxypropyl)amine in rats.

    PubMed

    Tsujiuchi, Toshifumi; Nakae, Dai; Konishi, Yoichi

    2014-03-01

    N-Nitrosobis(2-hydroxypropyl)amine (BHP) was first synthesized by Krüger et al. (1974), and has been shown to primarily induce pancreatic duct adenocarcinomas by a subcutaneous injection in Syrian hamsters. By contrast, the carcinogenic effect of BHP has been indicated at the different target organs in rats, namely the lung. When rats are received by an oral administration of BHP in drinking water for 25 weeks, a high incidence of lung carcinomas are induced, which include adenocarcinomas, squamous cell carcinomas and combined squamous cell and adenocarcinomas. So many similarities are observed in terms of not only histological appearances but also gene alterations between human and BHP-induced rat lung cancers. Moreover, the step by step development of lung lesions, from preneoplastic lesions to cancers in rat lung carcinogenesis by BHP offers a good model to investigate the mechanisms underlying the pathogenesis of lung cancers. Because data for genetic and epigenetic alterations have indeed been accumulated during the BHP-induced rat lung carcinogenesis, we will introduce them in this review and hence demonstrate that this lung carcinogenesis model provides a useful opportunity for the research on the pathogenesis of lung cancers of both humans and rats.

  14. Calcium accentuates injury induced by ethanol in human gastric cells.

    PubMed

    Kokoska, E R; Smith, G S; Deshpande, Y; Wolff, A B; Rieckenberg, C; Miller, T A

    1999-01-01

    The mechanism(s) whereby ethanol induces cellular injury remains poorly understood. Furthermore, the role of calcium in gastric mucosal injury under in vitro conditions is poorly defined. The major objectives of this study were to (1) define the temporal relationship between intracellular calcium accumulation induced by ethanol and cellular injury, (2) characterize the mechanism(s) whereby ethanol increases cellular calcium content, and (3) determine whether calcium removal would attenuate ethanol-induced cellular injury. Human gastric cells (AGS) were used for all experiments. Sustained intracellular calcium accumulation induced by ethanol, but not transient changes, preceded and directly correlated with cellular injury. Cells exposed to damaging concentrations of ethanol demonstrated an initial calcium surge that appeared to be a consequence of inositol 1,4,5-triphosphate (IP3) generation and subsequent internal store release followed by a sustained plateau resulting from extracellular calcium influx through store-operated calcium channels. Finally, both morphologic (cellular injury) and functional (clearance of bovine serum albumin) changes induced by ethanol were significantly attenuated when extracellular Ca(+&plus) influx was prevented, and further decreased when intracellular Ca(++) stores were depleted. These data indicate that calcium plays a significant role in cellular injury induced by ethanol.

  15. Protective effect of yellow tea extract on N-nitrosodiethylamine-induced liver carcinogenesis.

    PubMed

    Kujawska, Małgorzata; Ewertowska, Małgorzata; Adamska, Teresa; Ignatowicz, Ewa; Gramza-Michałowska, Anna; Jodynis-Liebert, Jadwiga

    2016-09-01

    Context Yellow tea containing the same catechins as other types of tea but in different proportions has been suggested to possess potent anticancer activities. Objective This study investigates the chemopreventive effect of yellow tea aqueous extract against N-nitrosodiethylamine (NDEA)-induced liver carcinogenesis in rats by employing histological and biochemical methods. Materials and methods Wistar rats were divided randomly into four groups: control (I), yellow tea (II), NDEA (III), and yellow tea + NDEA (IV). Groups II and IV were exposed via a diet to yellow tea extract in a concentration of 10 g/kg feed; groups III and IV received 0.01% NDEA in drinking water. The experiment lasted for 13 weeks. Results Daily intake of yellow tea in an average dose of 800 mg/kg b.w. alleviated the carcinogenic effect of NDEA as evidenced by reversed histopathological changes towards normal hepatocellular architecture and decreased lipid peroxidation, protein carbonyl formation, and DNA degradation by 64%, 37% and 15%, respectively, as compared with values obtained in NDEA alone-treated rats. Treatment with yellow tea extract caused protection of superoxide dismutase (SOD) and catalase (CAT); their activity was recovered by 47% and 12%, respectively, as compared with the NDEA-treated rats. Moreover, the extract normalized the NDEA-induced activity of paraoxonase 1 (PON1) and glutathione peroxidase (GPx), while a further increase in the level of reduced glutathione (GSH) was noticed. Conclusions On the basis of these findings, it can be concluded that treatment with yellow tea partially protected the livers of rats from NDEA-induced hepatocarcinogenesis and that its antioxidant activity contributed to this effect.

  16. Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice.

    PubMed

    Chen, Jayson X; Li, Guangxun; Wang, Hong; Liu, Anna; Lee, Mao-Jung; Reuhl, Kenneth; Suh, Nanjoo; Bosland, Maarten C; Yang, Chung S

    2016-02-01

    Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200 mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. Dietary tocopherols inhibit PhIP-induced prostate carcinogenesis in CYP1A-humanized mice

    PubMed Central

    Chen, Jayson X.; Li, Guangxun; Wang, Hong; Liu, Anna; Lee, Mao-Jung; Reuhl, Kenneth; Suh, Nanjoo; Bosland, Maarten C.; Yang, Chung S.

    2015-01-01

    Tocopherols, the major forms of vitamin E, exist as alpha-tocopherol (α-T), β-T, γ-T and δ-T. The cancer preventive activity of vitamin E is suggested by epidemiological studies, but recent large-scale cancer prevention trials with high dose of α-T yielded disappointing results. Our hypothesis that other forms of tocopherols have higher cancer preventive activities than α-T was tested, herein, in a novel prostate carcinogenesis model induced by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a dietary carcinogen, in the CYP1A-humanized (hCYP1A) mice. Treatment of hCYP1A mice with PhIP (200mg/kg b.w., i.g.) induced high percentages of mouse prostatic intraepithelial neoplasia (mPIN), mainly in the dorsolateral glands. Supplementation with a γ-T-rich mixture of tocopherols (γ-TmT, 0.3% in diet) significantly inhibited the development of mPIN lesions and reduced PhIP-induced elevation of 8-oxo-deoxyguanosine, COX-2, nitrotyrosine, Ki-67 and p-AKT, and the loss of PTEN and Nrf2. Further studies with purified δ-T, γ-T or α-T (0.2% in diet) showed that δ-T was more effective than γ-T or α-T in preventing mPIN formations and p-AKT elevation. These results indicate that γ-TmT and δ-T could be effective preventive agents of prostate cancer. PMID:26582657

  18. Asb6 upregulation by Areca nut extracts is associated with betel quid-induced oral carcinogenesis.

    PubMed

    Hung, Kai-Feng; Lai, Kuo-Chu; Liu, Tsung-Yun; Liu, Chung-Ji; Lee, Te-Chang; Lo, Jeng-Fan

    2009-06-01

    Betel quit (BQ) chewing is a popular habit, especially in southern and southeastern Asia. Areca nut extracts (ANE), the major components of BQ, have been documented to induce reactive oxygen species, and consequently to cause genetic damage. ANE usage is tightly linked to oral cancer; however, the details of the molecular mechanism that results in carcinogenesis remain unclear. Previously, we successfully established HaCaT cells surviving from the long-term exposure of sublethal doses of ANE (Lai KC, Lee TC. Genetic damage in cultured human keratinocytes stressed by long-term exposure to areca nut extracts. Mutat Res 2006;599:66-75). Here, we identified the upregulation of Asb6, a coupling protein to the APS adapter protein, which is involved in insulin signaling for glucose transportation, of normal keratinocytes and oral cancer cells under ANE treatment. Immunohistochemical analyses of Asb6 on oral squamous cell carcinoma (OSCC) tissues (n=57) demonstrated the positive correlation between Asb6 upregulation (cancerous tissues versus adjacent normal tissues) and clinicopathological features. We showed that the combination of ANE-enhanced Asb6 expression in vitro and Asb6 upregulation in OSCC patients leads to poor survival status. In conclusion, our results suggest that upregulated Asb6 could act as a prognostic marker for oral cancer.

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

    PubMed Central

    Konishi, Hidetomo; Asano, Naoki; Imatani, Akira; Kimura, Osamu; Kondo, Yutaka; Jin, Xiaoyi; Kanno, Takeshi; Hatta, Waku; Ara, Nobuyuki; Asanuma, Kiyotaka; Koike, Tomoyuki; Shimosegawa, Tooru

    2016-01-01

    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. PMID:27489358

  20. The effect of physical training on the N-methyl-N-nitrosourea-induced mammary carcinogenesis of Sprague–Dawley rats

    PubMed Central

    Siewierska, Katarzyna; Pula, Bartosz; Kobierzycki, Christopher; Haus, Dominik; Paslawska, Urszula; Cegielski, Marek; Dziegiel, Piotr; Podhorska-Okolow, Marzena; Wozniewski, Marek

    2015-01-01

    The impact of physical activity on carcinogenesis has been demonstrated in many studies. Taking into account the discrepant results of physical exercise on the cell proliferation and apoptosis of breast cancer, we aimed to examine the impact of physical training on N-methyl-N-nitrosourea-(MNU)-induced mammary carcinogenesis. Fifty female rats were divided into four groups according to the intensity of physical activity they undertook. The number of developed tumors, tumor volume, and histopathological diagnoses were noted. Apoptosis and cell proliferation were studied by the number of TUNEL-positive and Ki-67-expressing cells. We demonstrated a statistically significant decrease in the tumor number between all trained groups and the control group. The results were most pronounced in the group with a moderate intensity of training. Moreover, we showed a decrease in tumor volume as training intensity increased, though the differences were not statistically significant. The mean number of TUNEL-positive cancer cells was significantly higher in the training groups than in the control group. These data suggest that physical training, especially of moderate intensity, may alleviate MNU-induced mammary carcinogenesis. The results could suggest that physical exercise-induced apoptosis may be a protective mechanism. PMID:25990440

  1. The effect of physical training on the N-methyl-N-nitrosourea-induced mammary carcinogenesis of Sprague-Dawley rats.

    PubMed

    Malicka, Iwona; Siewierska, Katarzyna; Pula, Bartosz; Kobierzycki, Christopher; Haus, Dominik; Paslawska, Urszula; Cegielski, Marek; Dziegiel, Piotr; Podhorska-Okolow, Marzena; Wozniewski, Marek

    2015-11-01

    The impact of physical activity on carcinogenesis has been demonstrated in many studies. Taking into account the discrepant results of physical exercise on the cell proliferation and apoptosis of breast cancer, we aimed to examine the impact of physical training on N-methyl-N-nitrosourea-(MNU)-induced mammary carcinogenesis. Fifty female rats were divided into four groups according to the intensity of physical activity they undertook. The number of developed tumors, tumor volume, and histopathological diagnoses were noted. Apoptosis and cell proliferation were studied by the number of TUNEL-positive and Ki-67-expressing cells. We demonstrated a statistically significant decrease in the tumor number between all trained groups and the control group. The results were most pronounced in the group with a moderate intensity of training. Moreover, we showed a decrease in tumor volume as training intensity increased, though the differences were not statistically significant. The mean number of TUNEL-positive cancer cells was significantly higher in the training groups than in the control group. These data suggest that physical training, especially of moderate intensity, may alleviate MNU-induced mammary carcinogenesis. The results could suggest that physical exercise-induced apoptosis may be a protective mechanism. © 2015 by the Society for Experimental Biology and Medicine.

  2. Chemopreventive effect of zingerone against colon carcinogenesis induced by 1,2-dimethylhydrazine in rats.

    PubMed

    Vinothkumar, Rajenderan; Vinothkumar, Rajamanickam; Sudha, Mani; Nalini, Namasivayam

    2014-09-01

    Zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butane], one of the active phenolic components isolated from Zingiber officinale, has antioxidant and anticarcinogenic properties. In our study, we have evaluated the effect of different doses of zingerone on lipid peroxidation (thiobarbituric acid-reactive substances, lipid hydroxyl radical and conjugated dienes), tissue enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase), and nonenzymatic antioxidants (reduced glutathione, vitamin E, vitamin C), and also the formation of aberrant crypt foci (ACF) in male albino Wistar rats with colon cancer induced using 1,2-dimethylhydrazine (DMH). The rats were divided into six groups. Group 1 served as a control group and received a modified pellet diet; the rats in group 2 received a modified pellet diet along with zingerone (40 mg/kg b.w., orally every day); groups 3-6 were administered DMH (20 mg/kg b.w., subcutaneously) once a week for the first 4 weeks; and groups 4-6 received zingerone at three different doses of 10, 20 and 40 mg/kg b.w., respectively, every day for 16 weeks. Increased tumour incidence and ACF formation were accompanied by a decrease in the tissue lipid peroxidation, enzymatic and nonenzymatic antioxidant activities observed in the colon of DMH-treated rats. Supplementation with zingerone in DMH-treated rats led to a significant decrease in the tumour incidence and ACF formation with simultaneous modulation in the level of tissue lipid peroxidation and antioxidant status. Thus, in conclusion, we can suggest that zingerone effectively inhibits DMH-induced colon carcinogenesis in male Wistar rats.

  3. Effect of spices on lipid metabolism in 1,2-dimethylhydrazine-induced rat colon carcinogenesis.

    PubMed

    Nalini, N; Manju, V; Menon, V P

    2006-01-01

    Colon cancer is the second most common cancer among men and women worldwide. We investigated the effect of red chilli (Capsicum annum L.), cumin (Cuminum cyminum L.), and black pepper (Piper nigrum L.) on colon cancer induced in rats by a colon-specific carcinogen, 1,2-dimethylhydrazine (DMH). Colon cancer was induced by subcutaneous injection of DMH at a dosage of 20 mg/kg of body weight (15 doses, at 1-week intervals). The rats were continued with the standard pellet diet and supplemented red chilli [C. annum L., 0.015% (wt/wt) mixed with the diet], cumin seeds [C. cyminum L., 1.25% (wt/wt) mixed with the diet], and black pepper (P. nigrum L., 0.5% (wt/wt) mixed with the diet] throughout the experimental period. After the total experimental period of 32 weeks (including 2 weeks of acclimatization) the incidence and number of tumors in the colon were observed to be significantly higher in the rats administered DMH and/or red chillis, as compared with the cumin + DMH and black pepper + DMH groups. No tumors were observed in the control, cumin + DMH, or black pepper + DMH groups. The levels of fecal bile acids and neutral sterols in 24-hour fecal samples were significantly decreased in DMH + chilli-administered rats, while the excretion of fecal bile acids and neutral sterols was significantly increased in cumin + DMH- and black pepper + DMH-administered rats. In DMH-, chilli-, and chilli + DMH-administered rats the levels of cholesterol, cholesterol/phospholipid ratio, and 3-hydroxy-3-methylglutaryl-CoA reductase activity were decreased in cumin + DMH- and black pepper + DMH-treated rats. The phospholipid levels were reduced in the DMH, chilli, and chilli + DMH groups as compared with the cumin + DMH and black pepper + DMH groups. Our results show that chilli supplementation promotes colon carcinogenesis, whereas cumin or black pepper suppresses colon carcinogensis in the presence of the procarcinogen DMH.

  4. Deletion of cyclooxygenase-2 inhibits K-ras-induced lung carcinogenesis.

    PubMed

    Pan, Yong; Jiang, Yan; Tan, Lin; Ravoori, Murali K; Gagea, Mihai; Kundra, Vikas; Fischer, Susan M; Yang, Peiying

    2015-11-17

    The purpose of this study was to identify the role COX-2 plays in K-ras-induced lung carcinogenesis. We crossed COX-2-homozygous knockout mice with K-rasLA1 (G12D) expressing mice to obtain COX-2-deficient mice with K-ras expression (K-ras/COX-2(-/-) mice) and COX-2 wild type mice with K-ras expression (K-ras mice). At 3.5 months of age, the K-ras/COX-2(-/-) mice had significantly fewer lung adenocarcinomas and substantially smaller tumors than K-ras mice. K-ras/COX-2(-/-) mice also had significantly fewer bronchioalveolar hyperplasias than K-ras mice. Compared with lung tumors from K-Ras mice, the levels of prostaglandin E2 (PGE2) were significantly lower, whereas levels of the PGE2 metabolite 13,14-dihydro-15-keto-PGE2 were significantly higher, in lung tumors from K-ras/COX-2(-/-) mice. In addition, K-ras/COX-2(-/-) mice had strikingly lower rates of tumor cell proliferation and expressed less MEK and p-Erk1/2 protein than K-ras mice did. In line with this, knocking down COX-2 in mutant K-ras non-small cell lung cancer A549 cells reduced colony formation, PGE2 synthesis and ERK phosphorylation compared to that of vector control cells. Taken together, these findings suggest that COX-2 deletion contributes to the repression of K-ras-induced lung tumorigenesis by reducing tumor cell proliferation, decreasing the production of PGE2, and increasing the production of 13,14-dihydro-15-keto-PGE2, possibly via the MAPK pathway. Thus, COX-2 is likely important in lung tumorigenesis, and COX-2 and its product, PGE2, are potential targets for lung cancer prevention.

  5. DNA lesions, inducible DNA repair, and cell division: Three key factors in mutagenesis and carcinogenesis

    SciTech Connect

    Ames, B.N.; Shigenaga, M.K.; Gold, L.S.

    1993-12-01

    DNA lesions that escape repair have a certain probability of giving rise to mutations when the cell divides. Endogenous DNA damage is high: 10{sup 6} oxidative lesions are present per rat cell. An exogenous mutagen produces an increment in lesions over the background rate of endogenous lesions. The effectiveness of a particular lesion depends on whether it is excised by a DNA repair system and the probability that it gives rise to a mutation when the cell divides. When the cell divides, an unrepaired DNA lesion has a certain probability of giving rise to a mutation. Thus, an important factor in the mutagenic effect of an exogenous agent whether it is genotoxic or non-genotoxic, is the increment it causes over the background cell division rate (mitogenesis) in cells that appear to matter most in cancer, the stem cells, which are not on their way to being discarded. Increasing their cell division rate increases by high doses of chemicals. If both the rate of DNA lesions and cell division are increased, then there will be a multiplicative effect on mutagenesis (and carcinogenesis), for example, by high doses of a mutagen that also increases mitogenesis through cell killing. The defense system against reactive electrophilic mutagens, such as the glutathione transferases, are also almost all inducible and buffer cells against increments in active forms of chemicals that can cause DNA lesions. A variety of DNA repair defense systems, almost all inducible, buffer the cell against any increment in DNA lesions. Therefore, the effect of a particular chemical insult depends on the level of each defense, which in turn depends on the past history of exposure. Exogenous agents can influence the induction and effectiveness of these defenses. Defenses can be partially disabled by lack of particular micronutrients in the diet (e.g., antioxidants).

  6. The effect of childbirth on carcinogenesis of DMBA-induced breast cancer in female SD rats.

    PubMed

    Zhao, Ji-An; Chen, Jin-Jun; Ju, Ying-Chao; Wu, Jian-Hua; Geng, Cui-Zhi; Yang, Hui-Chai

    2011-11-01

    Many epidemiologic and clinical studies have indicated that the frequency of breast cancer was lower in parous women than in nulliparous women. Moreover, the incidence of breast cancer has been reported to be lower in women with early childbirth than in women with late childbirth. To verify the effect of childbirth and the age at first childbirth on carcinogenesis and progression of breast cancer, we induced breast cancer by 7,12-dimethylbenanthracene (DMBA) in 120 female Sprague-Dawley (SD) rats, and divided them into control or experimental (DMBA-treated) nulliparous, early childbirth, and late childbirth groups to observe the incidence, latency, and size of breast cancer. Argyrophilic nucleolar organizer regions (AgNOR) count and the expression of C-erbB-2, proliferating cell nuclear antigen (PCNA), Ki-67, and minichromosome maintenance protein 2 (MCM2) in breast cancer tissues were detected by immunohistochemistry. The breast cancer incidences were 95.0%, 16.7%, and 58.8% in the experimental nulliparous, early childbirth, and late childbirth groups, respectively (all P < 0.05). Between any two of these groups, the latency was significantly different, but tumor size was similar. AgNOR count and the expression of C-erbB-2, PCNA, Ki-67, and MCM2 were significantly higher in the experimental nulliparous group than in the experimental early or late childbirth groups (P < 0.05), but no significant differences were observed between the latter two groups. Taken together, the results suggest that childbirth, especially early childbirth, can reduce the incidence and postpone the onset of DMBA-induced breast cancer.

  7. Genetic Alterations in Gastric Cancer Associated with Helicobacter pylori Infection.

    PubMed

    Rivas-Ortiz, Claudia I; Lopez-Vidal, Yolanda; Arredondo-Hernandez, Luis Jose Rene; Castillo-Rojas, Gonzalo

    2017-01-01

    Gastric cancer is a world health problem and depicts the fourth leading mortality cause from malignancy in Mexico. Causation of gastric cancer is not only due to the combined effects of environmental factors and genetic variants. Recent molecular studies have transgressed a number of genes involved in gastric carcinogenesis. The aim of this review is to understand the recent basics of gene expression in the development of the process of gastric carcinogenesis. Genetic variants, polymorphisms, desoxyribonucleic acid methylation, and genes involved in mediating inflammation have been associated with the development of gastric carcinogenesis. Recently, these genes (interleukin 10, Il-17, mucin 1, β-catenin, CDX1, SMAD4, SERPINE1, hypoxia-inducible factor 1 subunit alpha, GSK3β, CDH17, matrix metalloproteinase 7, RUNX3, RASSF1A, TFF1, HAI-2, and COX-2) have been studied in association with oncogenic activation or inactivation of tumor suppressor genes. All these mechanisms have been investigated to elucidate the process of gastric carcinogenesis, as well as their potential use as biomarkers and/or molecular targets to treatment of disease.

  8. Gastroprotective effect of histamine and acid secretion on ammonia-induced gastric lesions in rats.

    PubMed

    Warzecha, Z; Dembiński, A; Brzozowski, T; Ceranowicz, P; Pajdo, R; Niemiec, J; Drozdowicz, D; Mitis-Musioł, M; Konturek, S J

    2000-09-01

    Previous studies have shown that ammonia produced by Helicobacter pylori urease or administrated intragastrically exhibits a toxic effect on the gastric mucosa. In the present study we investigated the influence of histamine and gastric acid secretion on ammonia (NH4OH)-induced gastric lesions. The gastric mucosa in rats was exposed to NH4OH (1.5 ml of 250 mM solution) under basal conditions, after administration of histamine (1 mg/kg), urea with urease, and ranitidine (40 mg/kg subcutaneously) given alone or in combination. We measured the area of gastric lesions, gastric blood flow (GBF), plasma gastrin concentration, DNA synthesis, gastric acid secretion and gastric luminal concentration of PGE2. Application of NH4OH resulted in the formation of acute gastric lesions. This effect was accompanied by a fall in GBF, a rise in gastric pH, and a reduction in mucosal DNA synthesis. Administration of histamine 30 min prior to NH4OH reduced the area of gastric lesions. This was accompanied by an increase in GBF, DNA synthesis, and prostaglandin E2 (PGE2) production. Ranitidine given prior to NH4OH enhanced gastric mucosa damage, and reduced GBF and DNA synthesis. This effect was accompanied by a reduction in gastric acid secretion. Ranitidine given prior to histamine abolished gastric acid secretion and the protective effect of histamine against NH4OH-induced damage; these effects were accompanied by a decrease in GBF, DNA synthesis, and concentration of PGE2. Pretreatment with 2% urea with urease given prior to NH4OH reduced NH4OH lesions. This effect was associated with an increase in gastric acid secretion, gastric generation of PGE2, GBF, and DNA synthesis. Ranitidine given prior to urea with urease inhibited gastric acid secretion and the gastroprotective effect of urea-urease gastroprotection. Histamine and gastric secretion exhibit a protective effect against ammonia-induced gastric lesions. This effect appears to depend upon the stimulation of gastric acid

  9. Inhibitory effects of voluntary running wheel exercise on UVB-induced skin carcinogenesis in SKH-1 mice.

    PubMed

    Michna, Laura; Wagner, George C; Lou, You-Rong; Xie, Jian-Guo; Peng, Qing-Yun; Lin, Yong; Carlson, Kirsten; Shih, Weichung Joe; Conney, Allan H; Lu, Yao-Ping

    2006-10-01

    Earlier studies showed that oral administration of green tea or caffeine to SKH-1 mice inhibited ultraviolet B light (UVB)-induced skin carcinogenesis, decreased dermal fat thickness and increased locomotor activity. In the present study, the effects of voluntary running wheel exercise on thickness of dermal fat as well as on UVB-induced tumorigenesis in SKH-1 mice were studied in UVB-initiated high-risk and UVB-induced complete carcinogenesis models. In the high-risk model, animals were exposed to UVB (30 mJ/cm(2)) 3 times/week for 16 weeks. For 14 weeks subsequent to UVB exposure, half of the animals had access to running wheels in their cages whereas the other half did not. In the complete carcinogenesis model, animals were exposed to UVB (30 mJ/cm(2)) 2 times/week for 33 weeks. From the beginning, half of the animals had access to running wheels whereas the other half did not. At the conclusion of each study, body weights were not different between groups, although animals with running wheels consumed significantly more food and water than animals without running wheels. In addition, animals with running wheels had decreases in parametrial fat pad weight and thickness of the dermal fat layer. In both UVB-initiated high-risk and complete carcinogenesis models, voluntary running wheel exercise delayed the appearance of tumors, decreased the number of tumors per mouse and decreased tumor volume per mouse. Histopathology studies revealed that running wheel exercise decreased the number of non-malignant tumors (primarily keratoacanthomas) by 34% and total tumors per mouse by 32% in both models, and running wheel exercise decreased the formation of squamous cell carcinomas in the UVB-induced complete carcinogenesis model by 27%. In addition, the size of keratoacanthomas and squamous cell carcinomas were decreased substantially in both models. The effects described here indicate that voluntary running wheel exercise inhibits UVB-induced skin tumorigenesis and may also

  10. Sensations induced by medium and long chain triglycerides: role of gastric tone and hormones

    PubMed Central

    Barbera, R; Peracchi, M; Brighenti, F; Cesana, B; Bianchi, P; Basilisco, G

    2000-01-01

    BACKGROUND—The relative roles of gastric relaxation and the neuroendocrine signals released by the small intestine in the perception of nutrient induced sensations are controversial. The different effects of long chain (LCT) and medium chain (MCT) triglyceride ingestion on perception, gastric relaxation, and hormonal release may help to elucidate the mechanisms underlying nutrient induced sensations.
AIMS—To compare the effects of intraduodenal LCT and MCT infusions on perception, gastric tone, and plasma gut hormone levels in healthy subjects.
SUBJECTS—Nine fasting healthy volunteers.
METHODS—The subjects received duodenal infusions of saline followed by LCTs and MCTs in a randomised order on two different days. The sensations were rated on a visual analogue scale. Gastric tone was measured using a barostat, and plasma gut hormone levels by radioimmunoassay.
RESULTS—LCT infusion increased satiation scores, reduced gastric tone, and increased the levels of plasma cholecystokinin, gastric inhibitory polypeptide, neurotensin, and pancreatic polypeptide. MCT infusion reduced gastric tone but did not significantly affect perception or plasma gut hormone levels. LCTs produced greater gastric relaxation than MCTs.
CONCLUSIONS—The satiation induced by intraduodenal LCT infusion seems to involve changes in gastric tone and plasma gut hormone levels. The gastric relaxation induced by MCT infusion, together with the absence of any significant change in satiation scores and plasma hormone levels, suggests that, at least up to a certain level, gastric relaxation is not sufficient to induce satiation and that nutrient induced gastric relaxation may occur through cholecystokinin independent mechanisms.


Keywords: gastric tone; triglyceride; hormones; satiation; cholecystokinin; nutrients PMID:10601051

  11. Viral Carcinogenesis.

    PubMed

    Smith, A J; Smith, L A

    2016-01-01

    Cancer has been recognized for thousands of years. Egyptians believed that cancer occurred at the will of the gods. Hippocrates believed human disease resulted from an imbalance of the four humors: blood, phlegm, yellow bile, and black bile with cancer being caused by excess black bile. The lymph theory of cancer replaced the humoral theory and the blastema theory replaced the lymph theory. Rudolph Virchow was the first to recognize that cancer cells like all cells came from other cells and believed chronic irritation caused cancer. At the same time there was a belief that trauma caused cancer, though it never evolved after many experiments inducing trauma. The birth of virology occurred in 1892 when Dimitri Ivanofsky demonstrated that diseased tobacco plants remained infective after filtering their sap through a filter that trapped bacteria. Martinus Beijerinck would call the tiny infective agent a virus and both Dimitri Ivanofsky and Marinus Beijerinck would become the fathers of virology. Not to long thereafter, Payton Rous founded the field of tumor virology in 1911 with his discovery of a transmittable sarcoma of chickens by what would come to be called Rous sarcoma virus or RSV for short. The first identified human tumor virus was the Epstein-Barr virus (EBV), named after Tony Epstein and Yvonne Barr who visualized the virus particles in Burkitt's lymphoma cells by electron microscopy in 1965. Since that time, many viruses have been associated with carcinogenesis including the most studied, human papilloma virus associated with cervical carcinoma, many other anogenital carcinomas, and oropharyngeal carcinoma. The World Health Organization currently estimates that approximately 22% of worldwide cancers are attributable to infectious etiologies, of which viral etiologies is estimated at 15-20%. The field of tumor virology/viral carcinogenesis has not only identified viruses as etiologic agents of human cancers, but has also given molecular insights to all human

  12. Maté attenuates DNA damage and carcinogenesis induced by diethylnitrosamine and thermal injury in rat esophagus.

    PubMed

    Silva, Juliana Ferreira da; Bidinotto, Lucas Tadeu; Furtado, Kelly Silva; Salvadori, Daisy Maria Fávero; Rivelli, Diogo Pineda; Barros, Silvia Berlanga de Moraes; Rodrigues, Maria Aparecida Marchesan; Barbisan, Luis Fernando

    2009-07-01

    Drinking hot maté has been associated with risk for esophageal cancer in South America. Thus, the aims of this study were to evaluate the modifying effects of maté intake on DNA damage and esophageal carcinogenesis induced by diethylnitrosamine (DEN) and thermal injury (TI) in male Wistar rats. At the initiation phase of carcinogenesis, rats were treated with DEN (8 x 80 mg/kg) and submitted to TI (water at 65 degrees C, 1 ml/rat, instilled into the esophagus). Concomitantly, the animals received maté (2.0%w/v) for 8 weeks. Samples of peripheral blood were collected 4h after the last DEN application for DNA damage analysis. At weeks 8 and 20, samples from esophagus and liver were also collected for histological and immunohistochemical analysis. Maté significantly decreased DNA damage in leukocytes, cell proliferation rates in both esophagus and liver and the number of preneoplastic liver lesions from DEN/TI-treated animals at week 8. A significant lower incidence of esophageal papillomas and liver adenomas and tumor multiplicity was observed in the animals previously treated with maté at week 20. Thus, maté presented protective effects against DNA damage and esophageal and liver carcinogenesis induced by DEN.

  13. Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase.

    PubMed Central

    Govindarajan, Baskaran; Klafter, Robert; Miller, Mark Steven; Mansur, Claire; Mizesko, Melissa; Bai, Xianhe; LaMontagne, Kenneth; Arbiser, Jack L.

    2002-01-01

    BACKGROUND: Implantation of foreign materials into mice and humans has been noted to result in the appearance of soft tissue sarcomas at the site of implantation. These materials include metal replacement joints and Dacron vascular grafts. In addition, occupational exposure to nickel has been shown to result in an increased risk of carcinogenesis. The molecular mechanisms of foreign body-induced carcinogenesis are not fully understood. MATERIALS AND METHODS: In order to gain insight into these mechanisms, we implanted nickel sulfide into wild type C57BL/6 mice as well as a mouse heterozygous for the tumor suppressor gene, p53. Malignant fibrous histiocytomas arose in all mice, and we have characterized the profile of tumor suppressor genes and signal transduction pathways altered in these cells. RESULTS: All tumors demonstrated hypermethylation of the tumor suppressor gene p16, as well as activation of the mitogen activated protein kinase (MAP kinase) signaling pathway. This knowledge may be beneficial in the prevention and treatment of tumors caused by foreign body implantation. CONCLUSIONS: Oxidative stress induced by nickel sulfide appears to cause loss of p16 and activation of MAP kinase signaling. These findings support the hypothesis of synergistic interactions between MAP kinase activation and p16 loss in carcinogenesis. PMID:11984000

  14. Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats.

    PubMed

    Tsuchigauchi, Takeshi; Takahashi, Tetsuyuki; Ohnishi, Takamasa; Ogawa, Hirohisa; Bando, Yoshimi; Uehara, Hisanori; Takizawa, Tamotsu; Kaneda, Shinya; Nakai, Tokiko; Shiota, Hiroshi; Izumi, Keisuke

    2009-08-01

    The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, is resistant to a variety of chemical carcinogenesis except liver and colon. In the present study, N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was examined in male and female LEC, Long-Evans Agouti (LEA), a sibling line of the LEC rat, and F344 rats (n=21). ENU was administered to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. Cerebral/spinal gliomas and trigeminal/spinal nerve schwannomas developed in both LEA and F344 rats at 30 weeks of age, but no nervous system tumors developed in LEC rats, the difference being statistically significant. Lung adenomas also developed in LEA and F344 rats, but not in LEC rats. Semiquantitative RT-PCR demonstrated that metallothionein (MT)1a, MT2 and O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA levels in the liver of LEC rats were higher than those in F344 and LEA rats. In addition, Western blot analysis showed that MT (MT1 plus MT2) in the liver of LEC rats was also higher than that in other strains. Present results suggest that high levels of MT and/or MGMT contribute to the resistance to nitrosamine-induced carcinogenesis in LEC rats.

  15. Chemopreventive action of mace (Myristica fragrans, Houtt) on methylcholanthrene-induced carcinogenesis in the uterine cervix in mice.

    PubMed

    Hussain, S P; Rao, A R

    1991-03-01

    The present paper reports the chemopreventive action of mace (aril covering the testa of the seed of Myristica fragrans) on 3-methylcholanthrene (MCA)-induced carcinogenesis in the uterine cervix of virgin, young adult, Swiss albino mice. Placement of cotton-thread impregnated with beeswax containing MCA (approximately 600 micrograms) inside the canal of the uterine cervix results in the appearance of precancerous and cancerous lesions in the cervical epithelium. In this experiment using the cervical carcinogenesis model system, if mace was administered orally at the dose level of 10 mg/mouse per day for 7 days before and 90 days following carcinogen thread insertion, the cervical carcinoma incidence, as compared with that of the control (73.9%), was 21.4%. This decline in the incidence of carcinoma was highly significant (P less than 0.001). The incidence of precancerous lesions did not display any definite association with different treatments.

  16. A Role for HSP70 in Protecting against Indomethacin-induced Gastric Lesions*

    PubMed Central

    Suemasu, Shintaro; Tanaka, Ken-Ichiro; Namba, Takushi; Ishihara, Tomoaki; Katsu, Takashi; Fujimoto, Mitsuaki; Adachi, Hiroaki; Sobue, Gen; Takeuchi, Koji; Nakai, Akira; Mizushima, Tohru

    2009-01-01

    A major clinical problem encountered with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, is gastrointestinal complications. Both NSAID-dependent cyclooxygenase inhibition and gastric mucosal apoptosis are involved in NSAID-produced gastric lesions, and this apoptosis is mediated by the endoplasmic reticulum stress response and resulting activation of Bax. Heat shock proteins (HSPs) have been suggested to protect gastric mucosa from NSAID-induced lesions; here we have tested this idea genetically. The severity of gastric lesions produced by indomethacin was worse in mice lacking heat shock factor 1 (HSF1), a transcription factor for hsp genes, than in control mice. Indomethacin administration up-regulated the expression of gastric mucosal HSP70. Indomethacin-induced gastric lesions were ameliorated in transgenic mice expressing HSP70. After indomethacin administration, fewer apoptotic cells were observed in the gastric mucosa of transgenic mice expressing HSP70 than in wild-type mice, whereas the gastric levels of prostaglandin E2 for the two were indistinguishable. This suggests that expression of HSP70 ameliorates indomethacin-induced gastric lesions by affecting mucosal apoptosis. Suppression of HSP70 expression in vitro stimulated indomethacin-induced apoptosis and activation of Bax but not the endoplasmic reticulum stress response. Geranylgeranylacetone induced HSP70 at gastric mucosa in an HSF1-dependent manner and suppressed the formation of indomethacin-induced gastric lesions in wild-type mice but not in HSF1-null mice. The results of this study provide direct genetic evidence that expression of HSP70 confers gastric protection against indomethacin-induced lesions by inhibiting the activation of Bax. The HSP inducing activity of geranylgeranylacetone seems to contribute to its gastroprotective activity against indomethacin. PMID:19439408

  17. Analysis of plasma metabolic biomarkers in the development of 4-nitroquinoline-1-oxide-induced oral carcinogenesis in rats

    PubMed Central

    KONG, XIANGLI; YANG, XIAOQIN; ZHOU, JINGLIN; CHEN, SIXIU; LI, XIAOYU; JIAN, FAN; DENG, PENGCHI; LI, WEI

    2015-01-01

    The aim of the present study was to identify time-dependent changes in the expression of metabolic biomarkers during the various stages of oral carcinogenesis to provide an insight into the sequential mechanism of oral cancer development. An 1H nuclear magnetic resonance (NMR)-based metabolomics approach was used to analyze the blood plasma samples of Sprague-Dawley rats exhibiting various oral lesions induced by the administration of 4-nitroquinoline-1-oxide (4NQO) in drinking water. The 1H NMR spectra were processed by principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) to determine the metabolic differences between the three developmental stages of oral mucosa cancer (health, oral leukoplakia [OLK] and oral squamous cell carcinoma [OSCC]). The variable importance in projection (VIP) score derived from the PLS-DA model was used to screen for important metabolites, whose significance was further verified through analysis of variance (ANOVA). Data from the present study indicated that 4NQO-induced rat oral carcinogenesis produced oral pre-neoplastic and neoplastic lesions and provided an effective model for analyzing sequential changes in the 1H NMR spectra of rat blood plasma. The 1H NMR-based metabolomics approach clearly differentiates between healthy, OLK and OSSC rats in the PCA and PLS-DA models. Furthermore, lactic acid, choline, glucose, proline, valine, isoleucine, aspartic acid and 2-hydroxybutyric acid demonstrated VIP>1 in the PLS-D model and P<0.05 with ANOVA. It was also identified that increases in lactic acid, choline and glucose, and decreases in proline, valine, isoleucine, aspartic acid and 2-hydroxybutyric acid may be relative to the characteristic mechanisms of oral carcinogenesis. Therefore, these plasma metabolites may serve as metabolic biomarkers in oral carcinogenesis and assist in the early diagnosis and preventive treatment of oral cancer. PMID:25435976

  18. Influence of extraneous supplementation of zinc on trace elemental profile leading to prevention of dimethylhydrazine-induced colon carcinogenesis.

    PubMed

    Chadha, Vijayta Dani; Garg, M L; Dhawan, D

    2010-10-01

    Trace elemental analyses of cancerous tissue is a less explored field of inquiry in cancer research. If the deficiency or excess of a particular trace element can be linked to the cancer, studies can be initiated to see its controlled administration to check the growth of cancer. The present study explored the prophylactic potential of zinc in experimental colon carcinogenesis and also its interaction with other trace metals, which gets altered during the development of colon cancer. Rats were segregated into four groups viz., normal control, dimethylhydrazine (DMH) treated, zinc treated, DMH+zinc treated. Initiation and induction of colon carcinogenesis was achieved through weekly subcutaneous injections of DMH (30 mg/Kg body weight) dissolved in 1 mM EDTA-normal saline (pH 6.5), for 8 and 16 weeks, respectively. Zinc was supplemented at a dose level of 227 mg/L in drinking water, for 8 and 16 weeks. The elemental analyses of colonic samples were carried out using Energy Dispersive X-Ray Fluorescence technique (EDXRF). Zinc administration to DMH treated rats significantly decreased the tumor incidence, tumor multiplicity with simultaneous decrement in tumor size. EDXRF studies revealed that the concentrations of the elements zinc, chromium, manganese and copper were decreased, whereas the concentration levels of iron were found to be increased in the colon tissues following 8 and 16 weeks of DMH treatment. However, zinc supplementation to DMH-treated rats significantly improved the altered levels of elements when compared to DMH-treated animals indicating the chemopreventive role of zinc. In conclusion, DMH induced colon carcinogenesis is accompanied by altered trace element profile and zinc has a positive beneficial effect against chemically-induced colonic carcinogenesis.

  19. Enhanced levels of glutathione and protein glutathiolation in rat tongue epithelium during 4-NQO-induced carcinogenesis.

    PubMed

    Huang, Zhishan; Komninou, Despina; Kleinman, Wayne; Pinto, John T; Gilhooly, Elaine M; Calcagnotto, Ana; Richie, John P

    2007-04-01

    High glutathione (GSH) levels are commonly found in oral tumors and are thought to play an important role in tumorigenesis. While posttranslational binding of GSH to cellular proteins (protein glutathiolation) has recently been recognized as an important redox-sensitive regulatory mechanism, no data currently exist on this process during carcinogenesis. Our goal was to determine the effects of 4-nitroquinoline-N-oxide (4-NQO)-induced carcinogenesis on tongue levels of protein-bound and free GSH and related thiols in the rat. Male F-344 rats (6 weeks of age) were administered either 4-NQO (20 ppm) in drinking water or tap water alone (controls) for 8 weeks. Twenty-four weeks after cessation of 4-NQO, squamous cell carcinomas of the tongue were observed in all rats. The levels of both free and bound GSH in tumors, as well as in adjacent tissues, were 2- to 3-fold greater than in tongue epithelium from control rats (p < 0.05). Prior to tumor formation, at 8 weeks after cessation of 4-NQO, hyperplasia, dysplasia and carcinoma in situ were observed in 100%, 25% and 12.5% of 4-NQO-treated rats, respectively. At this early stage of carcinogenesis, levels of free and bound GSH were increased 50% compared with tongue tissues from control rats (p<0.05). Glutathione disulfide (GSSG) levels were also 2-fold greater in tongue tissues from 4-NQO treated vs. control rats (p<0.05). Altogether, these results suggest that protein glutathiolation, together with GSH and GSSG levels, are induced during oral carcinogenesis in the rat possibly as a result of enhanced levels of oxidative stress.

  20. Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

    PubMed Central

    Tanaka, Takuji; Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei; Mori, Takayuki; Watanabe, Naoki; Naiki, Takafumi; Moriwaki, Hisataka; Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi

    2014-01-01

    Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation. PMID:25050571

  1. Mucosal adaptation to aspirin induced gastric damage in humans. Studies on blood flow, gastric mucosal growth, and neutrophil activation.

    PubMed Central

    Konturek, J W; Dembinski, A; Stoll, R; Domschke, W; Konturek, S J

    1994-01-01

    The gastropathy associated with the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin is a common side effect of this class of drugs, but the precise mechanisms by which they cause mucosal damage have not been fully explained. During continued use of an injurious substance, such as aspirin, the extent of gastric mucosal damage decreases and this phenomenon is named gastric adaptation. To assess the extent of mucosal damage by aspirin and subsequent adaptation the effects of 14 days of continuous, oral administration of aspirin (2 g per day) to eight healthy male volunteers was studied. To estimate the rate of mucosal damage, gastroscopy was performed before (day 0) and at days 3, 7, 14 of aspirin treatment. Gastric microbleeding and gastric mucosal blood flow were measured using laser Doppler flowmeter and mucosal biopsy specimens were taken for the estimation of tissue DNA synthesis and RNA and DNA concentration. In addition, the activation of neutrophils in peripheral blood was assessed by measuring their ability to associate with platelets. Aspirin induced acute damage mainly in gastric corpus, reaching at day 3 about 3.5 on the endoscopic Lanza score but lessened to about 1.5 at day 14 pointing to the occurrence of gastric adaptation. Mucosal blood flow increased at day 3 by about 50% in the gastric corpus and by 88% in the antrum. The in vitro DNA synthesis and RNA concentration, an index of mucosal growth, were reduced at day 3 but then increased to reach about 150% of initial value at the end of aspirin treatment. It is concluded that the treatment with aspirin in humans induces gastric adaptation to this agent, which entails the increase in mucosal blood flow, the rise in neutrophil activation, and the enhancement in mucosal growth. PMID:7959223

  2. Enhanced glycolysis, regulated by HIF-1α via MCT-4, promotes inflammation in arsenite-induced carcinogenesis.

    PubMed

    Luo, Fei; Zou, Zhonglan; Liu, Xinlu; Ling, Min; Wang, Qingling; Wang, Qi; Lu, Lu; Shi, Le; Liu, Yonglian; Liu, Qizhan; Zhang, Aihua

    2017-06-01

    Arsenite is well established as a human carcinogen, but the molecular mechanisms leading to arsenite-induced carcinogenesis are complex and elusive. Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite is unknown. We have found that, with chronic exposure to arsenite, L-02 cells undergo a metabolic shift to glycolysis. In liver cells exposed to arsenite, hypoxia inducible factor-1α (HIF-1α) and monocarboxylate transporter-4 (MCT-4) are over-expressed. MCT-4, directly mediated by HIF-1α, maintains a high level of glycolysis, and the enhanced glycolysis promotes pro-inflammatory properties, which are involved in arsenite carcinogenesis. In addition, serum lactate and cytokines are higher in arsenite-exposed human populations, and there is a positive correlation between them. Moreover, there is a positive relationship between lactate and cytokines with arsenic in hair. In sum, these findings indicate that MCT-4, mediated by HIF-1α, enhances the glycolysis induced by arsenite. Lactate, the end product of glycolysis, is released into the extracellular environment. The acidic microenvironment promotes production of pro-inflammatory cytokines, which contribute to arsenite-induced liver carcinogenesis. These results provide a link between the induction of glycolysis and inflammation in liver cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. The M2 macrophages induce autophagic vascular disorder and promote mouse sensitivity to urethane-related lung carcinogenesis.

    PubMed

    Li, G-G; Guo, Z-Z; Ma, X-F; Cao, N; Geng, S-N; Zheng, Y-Q; Meng, M-J; Lin, H-H; Han, G; Du, G-J

    2016-06-01

    Tumor vessels are known to be abnormal, with typically aberrant, leaky and disordered vessels. Here, we investigated whether polarized macrophage phenotypes are involved in tumor abnormal angiogenesis and what is its mechanism. We found that there was no difference in chemotaxis of polarized M1 and M2 macrophages to lewis lung carcinoma (LLC) cells and that either M1 or M2 macrophage-conditioned media had no effect on LLC cell proliferation. Unexpectedly, the M2 but not M1 macrophage-conditioned media promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and simultaneously increased endothelial cell permeability in vitro and angiogenic index in the chick embryo chorioallantoic membrane (CAM). The treatment with M2 but not M1 macrophage-conditioned media increased autophagosomes as well as microtubule-associated protein light chain 3B (LC3-B) expression (a robust marker of autophagosomes) but decreased p62 protein expression (a selective autophagy substrate) in HUVECs, the treatment with chloroquine that blocked autophagy abrogated the abnormal angiogenic efficacy of M2 macrophage-conditioned media. These results were confirmed in urethane-induced lung carcinogenic progression. Urethane-induced lung carcinogenesis led to more M2 macrophage phenotype and increased abnormal angiogenesis concomitant with the upregulation of LC3-B and the downregulation of p62. Clodronate liposome-induced macrophage depletion, chloroquine-induced autophagic prevention or salvianolic acid B-induced vascular protection decreased abnormal angiogenesis and lung carcinogenesis. In addition, we found that the tendency of age-related M2 macrophage polarization also promoted vascular permeability and carcinogenesis in urethane carcinogenic progression. These findings indicate that the M2 macrophages induce autophagic vascular disorder to promote lung cancer progression, and the autophagy improvement represents an efficacious strategy for abnormal angiogenesis and cancer

  4. Role of hormone imbalance in transplacental carcinogenesis induced in Syrian golden hamsters by sex hormones.

    PubMed

    Rustia, M

    1979-05-01

    Data are presented from studies on Syrian golden hamsters with the ENU precursors, EU, and NaNO2, given transplacentally and in adulthood, and with transplacentally administered DES. Hormone modification by gonadectomy of offspring prenatally exposed to ENU caused a significantly greater incidence and multiplicity of PNS neoplasms and other tumor types in orchidectomized males, compared with intact males, and in ovariectomized and intact females. That PNS tumors in gonadectomized males appeared within a significantly shorter latency period indicated that endogenously generated androgens inhibited neoplastic development. The endocrine imbalance also induced a higher incidence of neoplasia in other tissues and organs, e.g., skin melanomas, thyroid and adrenal cortex tumors, and notably gliomas in the CNS of ovariectomized female siblings. Exposure to single doses of ENU on days 12, 13, 14, and/or 15 caused PNS tumors predominantly in females and with an increased frequency in progeny treated during the final days of gestation. The spectrum of neoplasms was greater and their incidence significant in ENU-treated adult hamsters; the tumor types different from those of transplacentally treated animals (i.e., vascular, vaginal, and ovarian tumors and fore-stomach papillomas were seen). Determining factors in carcinogenesis at the time of carcinogen treatment possibly included stage of ontogenic development, degree of cell differentiation, hormone state of host, age, total dose, and duration of treatment. DES results indicated that the haster may be a useful model for reproducing lesions similar to those observed in children of mothers treated with this drug during pregnancy.

  5. Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review)

    PubMed Central

    FERNANDES, JOSÉ VERÍSSIMO; DE MEDEIROS FERNANDES, THALES ALLYRIO ARAÚJO; DE AZEVEDO, JENNER CHRYSTIAN VERÍSSIMO; COBUCCI, RICARDO NEY OLIVEIRA; DE CARVALHO, MARIA GORETTI FREIRE; ANDRADE, VANIA SOUSA; DE ARAÚJO, JOSÉLIO MARIA GALVÃO

    2015-01-01

    Inflammation is a defense strategy against invading agents and harmful molecules that is activated immediately following a stimulus, and involves the release of cytokines and chemokines, which activate the innate immune response. These mediators act together to increase blood flow and vascular permeability, facilitating recruitment of effector cells to the site of injury. Following resolution of the injury and removal of the stimulus, inflammation is disabled, but if the stimulus persists, inflammation becomes chronic and is strongly associated with cancer. This is likely to be due to the fact that the inflammation leads to a wound that does not heal, requiring a constant renewal of cells, which increases the risk of neoplastic transformation. Debris from phagocytosis, including the reactive species of oxygen and nitrogen that cause damage to DNA already damaged by the leukotrienes and prostaglandins, has an impact on inflammation and various carcinogenic routes. There is an association between chronic inflammation, persistent infection and cancer, where oncogenic action is mediated by autocrine and paracrine signals, causing changes in somatic cells under the influence of the microbial genome or of epigenetic factors. Among the infectious agents associated with cancer, certain genotypes of human papillomavirus (HPV) stand out. HPV is responsible for virtually all cases of cervical cancer and a lower proportion of cancers of the vagina, vulva, anus, penis and a number of extragenital cancers. In the present review, recent advances in the mechanisms involved in the inflammatory response are presented with their participation in the process of carcinogenesis, emphasizing the role of chronic inflammation in the development of HPV-induced cervical cancer. PMID:25663851

  6. Tobacco Smoke-Induced Immunologic Changes May Contribute to Oral Carcinogenesis

    PubMed Central

    Schierl, Michael; Patel, Daxesh; Ding, Wanhong; Kochhar, Amit; Adhami, Katayun; Zhou, Xi Kathy; Dannenberg, Andrew J.; Granstein, Richard D.

    2014-01-01

    Objective To determine if tobacco smoke (TS), a risk factor for cancers of the aerodigestive tract, may contribute to oral carcinogenesis, in part, by suppressing local immunity. Methods Mice were placed in plexiglass holders in which they breathed TS through the nose and mouth for 1 hour daily for 21 days. Control mice breathed room air in the same manner. One day after the last exposure, mice were immunized by application of oxazolone to each buccal mucosa. Control mice were mock-immunized by application of vehicle alone. Five days later, all mice were challenged on the ears with oxazolone and 24 hour ear swelling assessed as contact hypersensitivity (CHS). Results Mice exposed to TS had a significantly smaller CHS response compared to controls. When subsequently re-immunized on the glabrous skin, mice originally primed through TS-exposed mucosa could not be fully immunized, indicating induction of immunologic tolerance by exposure to hapten through TS-perturbed mucosa. Immunocompetent mice exposed to TS in this manner and challenged by submucosal placement of a syngeneic malignant tumor had significantly increased tumor growth over time compared to controls. No difference in growth rate was observed when the experiment was performed with NK cell-deficient, SCID mice. Additionally, exposure of epidermal Langerhans cells in vitro to an aqueous extract of TS impaired their ability to undergo maturation and to present antigen to responsive T cells. Conclusions Immunologic changes induced in the oral cavity by exposure to TS may play a role in the development of oral cancers. PMID:24322330

  7. Early diagnosis of colorectal cancer in rats with DMH induced carcinogenesis by means of urine autofluorescence analysis.

    PubMed

    Šteffeková, Zuzana; Birková, Anna; Bomba, Alojz; Mareková, Mária

    2014-01-01

    Cancer is one of the most highlighted topics of current research. Early detection of this disease allows more effective therapy, hence higher chance of cure. Application of fluorescence spectral techniques into oncological diagnostic is one of the potential alternatives. Chemically induced carcinogenesis in rats is widely used model for exploration of various aspects of colorectal cancer. This study shows value of discriminate analysis of urine fluorescent fingerprint between healthy control group of rats and those with dimethylhydrazine induced early lesions of colorectal cancer. Using fluorescence spectroscopy, significant difference (P < 0.05) between both of group was achieved.

  8. A Rat Model to Study the Effects of Diet-Induced Obesity on Radiation-Induced Mammary Carcinogenesis.

    PubMed

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Daino, Kazuhiro; Morioka, Takamitsu; Nishimura, Yukiko; Uemura, Hiroji; Akimoto, Kenta; Furukawa, Yuki; Fukushi, Masahiro; Wakabayashi, Keiji; Mutoh, Michihiro; Shimada, Yoshiya

    2016-05-01

    A detailed understanding of the relationship between radiation-induced breast cancer and obesity is needed for appropriate risk management and to prevent the development of a secondary cancer in patients who have been treated with radiation. Our goal was to develop an animal model to study the relationship by combining two existing Sprague-Dawley rat models of radiation-induced mammary carcinogenesis and diet-induced obesity. Female rats were fed a high-fat diet for 4 weeks and categorized as obesity prone or obesity resistant based on their body weight at 7 weeks of age, at which time the rats were irradiated with 4 Gy. Control rats were fed a standard diet and irradiated at the same time and in the same manner. All rats were maintained on their initial diets and assessed for palpable mammary cancers once a week for the next 30 weeks. The obesity-prone rats were heavier than those in the other groups. The obesity-prone rats were also younger than the other animals at the first detection of mammary carcinomas and their carcinoma weights were greater. A tendency toward higher insulin and leptin blood levels were observed in the obesity-prone rats compared to the other two groups. Blood angiotensin II levels were elevated in the obesity-prone and obesity-resistant rats. Genes related to translation and oxidative phosphorylation were upregulated in the carcinomas of obesity-prone rats. Expression profiles from human breast cancers were used to validate this animal model. As angiotensin is potentially an important factor in obesity-related morbidities and breast cancer, a second set of rats was fed in a similar manner, irradiated and then treated with an angiotensin-receptor blocker, losartan and candesartan. Neither blocker altered mammary carcinogenesis; analyses of losartan-treated animals indicated that expression of renin in the renal cortex and of Agtr1a (angiotensin II receptor, type 1) in cancer tissue was significantly upregulated, suggesting the presence of

  9. Efficacy of the potential chemopreventive agent, hesperetin (citrus flavanone), on 1,2-dimethylhydrazine induced colon carcinogenesis.

    PubMed

    Aranganathan, S; Nalini, N

    2009-10-01

    Our current study is an effort to identify a potent chemopreventive agent against colon cancer. Here we have investigated the efficacy of hesperetin on tissue lipid peroxidation, antioxidant defense system and colonic histoarchitecture in male Wistar rats in colon carcinogenesis. Rats in groups 3, 4, 5 and 6 were treated with DMH (20 mg kg body weight s.c.) once a week for 15 weeks. Group 1 rats received modified pellet diet and served as control; group 2 received modified pellet diet along with hesperetin (20mg/kg body weight, p.o., every day); and hesperetin was given to the rats as in-group 2 during the initiation, post-initiation and entire period stages of colon carcinogenesis. Lipid peroxidation was studied by measuring the formation of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD), and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione reductase (GR), reduced glutathione (GSH), in the liver and colonic tissues of DMH administered rats. (1) Decreased levels of lipid peroxidation in the colonic tissues; (2) decreased activities of antioxidant enzymes SOD, CAT, GPX, GR and GSH levels in the tissues on DMH treatment. Hesperetin supplementation during the initiation, post-initiation and entire period stages of carcinogenesis significantly reversed these activities. These results indicate that hesperetin may be a potential chemopreventive agent against DMH-induced colon cancer.

  10. RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis

    PubMed Central

    Lesina, Marina; Wörmann, Sonja Maria; Diakopoulos, Kalliope Nina; Korneeva, Olga; Wimmer, Margit; Sperveslage, Jan; Demir, Ihsan Ekin; Kehl, Timo; Saur, Dieter; Heikenwälder, Mathias; Steiner, Jörg Manfred; Wang, Timothy Cragin; Sansom, Owen J.; Schmid, Roland Michael

    2016-01-01

    Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC. PMID:27454298

  11. erbB expression changes in ethanol and 7, 12- dimethylbenz (a) anthracene-induced oral carcinogenesis

    PubMed Central

    Jacinto-Alemán, Luis F.; García-Carrancá, Alejandro; Leyba-Huerta, Elba R.; Zenteno-Galindo, Edgar; Jiménez-Farfán, María D.

    2013-01-01

    Objetive: The aim of this study was to determine erbB expression in normal mucosa, oral dysplasia, and invasive carcinomas developed in the hamster’s buccal pouch chemical carcinogenesis model. Study design: Fifty Syrian golden hamsters were equally divided in five groups (A-E); two controls and three experimental group exposed to alcohol, DMBA, or both for 14 weeks. Number of tumors per cheek, volume, histological condition, erbB expression were determined and results were analyzed by the Mann–Whitney U and Dunn’s test. Results: Control groups and those exposed to alcohol (A, B and C respectively) only presented clinical and histological normal mucosa; while those exposed to DMBA or DMBA plus alcohol (D and E groups) developed dysplasia and invasive carcinomas. erbB2, erbB3, and erbB4 increased their expression in alcohol-exposed mucosa, dysplasia, and invasive carcinomas. We observed a similar expression level for erbB2 in dysplasia and carcinomas; while, erbB3 and erbB4 were similar only in carcinomas. Conclusion: The DMBA and alcohol can be considered as carcinogen and promoter for oral carcinogenesis. The erbB expression is different according to their histological condition, suggesting differential participation of the erbB family in oral carcinogenesis induced by alcohol and DMBA. Key words:erbB, 7,12- dimethylbenz(a)anthracene, oral squamous cell carcinoma. PMID:23229248

  12. Fyn is a redox sensor involved in solar ultraviolet light-induced signal transduction in skin carcinogenesis.

    PubMed

    Kim, J-E; Roh, E; Lee, M H; Yu, D H; Kim, D J; Lim, T-G; Jung, S K; Peng, C; Cho, Y-Y; Dickinson, S; Alberts, D; Bowden, G T; Einspahr, J; Stratton, S P; Curiel-Lewandrowski, C; Bode, A M; Lee, K W; Dong, Z

    2016-08-04

    Solar ultraviolet (UV) light is a major etiological factor in skin carcinogenesis, with solar UV-stimulated signal transduction inducing pathological changes and skin damage. The primary sensor of solar UV-induced cellular signaling has not been identified. We use an experimental system of solar simulated light (SSL) to mimic solar UV and we demonstrate that Fyn is a primary redox sensor involved in SSL-induced signal transduction. Reactive oxygen species (ROS) generated by SSL exposure directly oxidize Cys488 of Fyn, resulting in increased Fyn kinase activity. Fyn oxidation was increased in mouse skin after SSL exposure and Fyn-knockout mice formed larger and more tumors compared with Fyn wild-type mice when exposed to SSL for an extended period of time. Murine embryonic fibroblasts (MEFs) lacking Fyn and cells in which Fyn expression was knocked down were resistant to SSL-induced apoptosis. Furthermore, cells expressing mutant Fyn (C448A) were resistant to SSL-induced apoptosis. These findings suggest that Fyn acts as a regulatory nexus between solar UV, ROS and signal transduction during skin carcinogenesis.

  13. Experimental gastric ulcers induced by immobilization and electric shock of rats and their pharmacotherapy

    NASA Technical Reports Server (NTRS)

    Zabrodin, O. N.

    1980-01-01

    The mechanism of development of experimental gastric ulcers, induced in rats by combined immobilization and electric shock, was analyzed pharmacologically with peripheral neurotropic agents. It is concluded that: (1) The most marked preventive effect in the development of the experimentally induced gastric ulcers was displayed by agents capable of blocking the ascending activation system of the reticular formation. (2) Sympathetic fibers, which disrupt the trophism of the gastric wall, form the efferent portion of the reflex arc. (3) Gastric secretion does not appear to be the primary cause of ulceration.

  14. Helicobacter pylori-induced lymphonodular hyperplasia: a new cause of gastric outlet obstruction.

    PubMed

    Misra, S P; Misra, V; Dwivedi, M; Singh, P A

    1998-12-01

    A 30-year-old female was seen with symptoms and radiological evidence of gastric outlet obstruction. Endoscopic examination revealed findings suggestive of gastric outlet obstruction with nodularity of the antral mucosa leading to deformity of the pylorus. Endoscopic biopsies from the nodular antral mucosa showed presence of Helicobacter pylori-induced lymphonodular hyperplasia without evidence of mucosa-associated lymphoid tissue lymphoma. Anti-H. pylori therapy resulted in eradication of the H. pylori infection and the signs and symptoms of gastric outlet obstruction. The case demonstrates that H. pylori-induced lymphonodular hyperplasia can also cause gastric outlet obstruction. We believe this is the first such case to be reported.

  15. Aloe-emodin-induced apoptosis in human gastric carcinoma cells.

    PubMed

    Chen, Sheng-Hsuan; Lin, Kai-Yuan; Chang, Chun-Chao; Fang, Chia-Lang; Lin, Chih-Ping

    2007-11-01

    The purpose of this study was to investigate the anticancer effect of aloe-emodin, an anthraquinone compound present in the leaves of Aloe vera, on two distinct human gastric carcinoma cell lines, AGS and NCI-N87. We demonstrate that aloe-emodin induced cell death in a dose- and time-dependent manner. Noteworthy is that the AGS cells were generally more sensitive than the NCI-N87 cells. Aloe-emodin caused the release of apoptosis-inducing factor and cytochrome c from mitochondria, followed by the activation of caspase-3, leading to nuclear shrinkage and apoptosis. In addition, exposure to aloe-emodin suppressed the casein kinase II activity in a time-dependent manner and was accompanied by a reduced phosphorylation of Bid, a downstream substrate of casein kinase II and a pro-apoptotic molecule. These preclinical studies suggest that aloe-emodin represents a suitable and novel chemotherapeutic drug candidate for the treatment of human gastric carcinoma.

  16. [Acute gastric lesions induced by drinking water, in rats].

    PubMed

    Laudano, O M

    1994-01-01

    The ability of certain beverages and drinking waters to induce acute gastric lesions was studied and the measurement of their pH was performed. 1) Saline; 2) tap water; 3) well-water; 4) well water plus puritabs; 5) saline plus 2 Cl drips; 6) saline plus 4 Cl drops; 7) saline plus 8 Cl drops; 8) boiled water after 30 min; 9) apartment deposit water; 10) WC bowl water; 11) ice water; 12) Paraná river water (Northern Rosario); 13) Paraná river water (Southern Rosario); 14) rain water (Rosario); 15) rain water) countryside); 16) carbonated mineral water; 17) non-carbonated mineral water; 18) soda; 19) flavored electrolytic water I; 20) flavored electrolytic water II; and 21) cola drink. We can conclude that: 1) a remarkable variance in saline and tap water pH is observed. 2) Rain water and Paraná river water were slightly acid, in contrast electrolytic carbonated beverages and cola drink were strongly acid (pH 2.5). 3) Saline, pH 6.68; saline plus 2 Cl drops; and non-carbonated mineral water were the only beverages that did not induce acute gastric lesions in rats.

  17. Copper and resveratrol attenuates serum catalase, glutathione peroxidase, and element values in rats with DMBA-induced mammary carcinogenesis.

    PubMed

    Skrajnowska, Dorota; Bobrowska-Korczak, Barbara; Tokarz, Andrzej; Bialek, Slawomir; Jezierska, Ewelina; Makowska, Justyna

    2013-12-01

    In this paper, a hypothesis was assessed whether or not the intoxication with copper and supplementation with copper plus resveratrol would result in changes in the activities of catalase and glutathione peroxidase and moreover if the characteristic changes would appear in concentrations of copper, iron, calcium, magnesium, and zinc in the serum of rats with chemically induced carcinogenesis. Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet, were treated with copper (42.6 mg Cu/kg food as CuSO4·5H2O) or copper plus resveratrol (0.2 mg/kg body) via gavage for a period from 40 days until 20 weeks of age. In cancer groups, the rats were treated with a dose of 80 mg/body weight of 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) given in rapeseed oil at 50 and 80 days of age to induce mammary carcinogenesis. The control groups included the rats kept in the same conditions and fed with the same diet as the animals from the study groups, but not DMBA-treated. The activity of catalase significantly decreased in groups of rats with mammary carcinogenesis that were supplemented with copper (p < 0.05) or copper plus resveratrol (p < 0.001) in comparison with the control groups that received the same diets. In cancer groups of nonsupplemented rats, the increase of glutathione peroxidase activity was observed. The process of carcinogenesis and the applied supplementation significantly altered the concentrations of trace elements in serum, in particular as concerns iron and copper. The mean serum iron levels in rats with breast cancer were significantly lower than those in the control groups (p < 0.001). The mean serum copper levels significantly decreased in the groups of rats with mammary carcinogenesis that were supplemented with copper or copper plus resveratrol in comparison with the control groups that received the same diets (p < 0.001). The characteristic changes in iron content and the zinc/copper and zinc/iron ratios in blood

  18. Aqueous suspension of anise "Pimpinella anisum" protects rats against chemically induced gastric ulcers.

    PubMed

    Al Mofleh, Ibrahim A; Alhaider, Abdulqader A; Mossa, Jaber S; Al-Soohaibani, Mohammed O; Rafatullah, Syed

    2007-02-21

    To substantiate the claims of Unani and Arabian traditional medicine practitioners on the gastroprotective potential effect of a popular spice anise, "Pimpinella anisum L." on experimentally-induced gastric ulceration and secretion in rats. Acute gastric ulceration in rats was produced by various noxious chemicals including 80% ethanol, 0.2 mol/L NaOH, 25% NaCl and indomethacin. Anti-secretory studies were undertaken using pylorus-ligated Shay rat technique. Levels of gastric non-protein sulfhydryls (NP-SH) and wall mucus were estimated and gastric tissue was also examined histologically. Anise aqueous suspension was used in two doses (250 and 500 mg/kg body weight) in all experiments. Anise significantly inhibited gastric mucosal damage induced by necrotizing agents and indomethacin. The anti-ulcer effect was further confirmed histologically. In pylorus-ligated Shay rats, anise suspension significantly reduced the basal gastric acid secretion, acidity and completely inhibited the rumenal ulceration. On the other hand, the suspension significantly replenished ethanol-induced depleted levels of gastric mucosal NP-SH and gastric wall mucus concentration. Anise aqueous suspension possesses significant cytoprotective and anti-ulcer activities against experimentally-induced gastric lesions. The anti-ulcer effect of anise is possibly prostaglandin-mediated and/or through its anti-secretory and antioxidative properties.

  19. Aqueous suspension of anise “Pimpinella anisum” protects rats against chemically induced gastric ulcers

    PubMed Central

    Al Mofleh, Ibrahim A; Alhaider, Abdulqader A; Mossa, Jaber S; Al-Soohaibani, Mohammed O; Rafatullah, Syed

    2007-01-01

    AIM: To substantiate the claims of Unani and Arabian traditional medicine practitioners on the gastroprotective potential effect of a popular spice anise, “Pimpinella anisum L.” on experimentally-induced gastric ulceration and secretion in rats. METHODS: Acute gastric ulceration in rats was produced by various noxious chemicals including 80% ethanol, 0.2 mol/L NaOH, 25% NaCl and indomethacin. Anti-secretory studies were undertaken using pylorus-ligated Shay rat technique. Levels of gastric non-protein sulfhydryls (NP-SH) and wall mucus were estimated and gastric tissue was also examined histologically. Anise aqueous suspension was used in two doses (250 and 500 mg/kg body weight) in all experiments. RESULTS: Anise significantly inhibited gastric mu-cosal damage induced by necrotizing agents and indomethacin. The anti-ulcer effect was further confirmed histologically. In pylorus-ligated Shay rats, anise suspension significantly reduced the basal gastric acid secretion, acidity and completely inhibited the rumenal ulceration. On the other hand, the suspension significantly replenished ethanol-induced depleted levels of gastric mucosal NP-SH and gastric wall mucus concentration. CONCLUSION: Anise aqueous suspension possesses significant cytoprotective and anti-ulcer activities against experimentally-induced gastric lesions. The anti-ulcer effect of anise is possibly prostaglandin-mediated and/or through its anti-secretory and antioxidative properties. PMID:17373749

  20. Helicobacter pylori induces Snail expression through ROS-mediated activation of Erk and inactivation of GSK-3β in human gastric cancer cells.

    PubMed

    Ngo, Hoang-Kieu-Chi; Lee, Hee Geum; Piao, Juan-Yu; Zhong, Xiancai; Lee, Ha-Na; Han, Hyeong-Jun; Kim, Wonki; Kim, Do-Hee; Cha, Young-Nam; Na, Hye-Kyung; Surh, Young-Joon

    2016-12-01

    Helicobacter pylori (H. pylori) infection has been known to be implicated in human gastric carcinogenesis. Snail, the zinc-finger transcription factor known as a key inducer of changes in the cell shape and morphogenetic movement, is aberrantly overexpressed and correlates with lymph node metastasis in gastric cancer. In the present study, we investigated whether H. pylori could induce Snail activation to provoke these changes. Using a cell scatter assay, we noticed that human gastric cancer AGS cells infected with H. pylori underwent morphological changes as well as disruption of cell-cell interaction, which was then reversed by silencing of Snail by use of small interfering RNA (siRNA). In addition, infection with H. pylori resulted in an increased intracellular level of Snail in gastric cancer cells, which was abrogated in the presence of U0126 and LY294002, inhibitors of MEK/Erk and PI3K/Akt pathways, respectively. Cycloheximide pulse-chase experiments coupled with immunocytochemical analysis revealed that the induction of Snail by H. pylori was regulated at multiple levels, including increased transcription of Snail mRNA, inhibition of protein degradation, and enhancement of nuclear translocation of Snail. Pre-treatment of AGS cells with N-acetylcysteine, a well-known reactive oxygen species (ROS) scavenger, attenuated the H. pylori-induced activation of Erk, its binding to Snail promoter, inactivation of GSK-3β, and accumulation of Snail. Collectively, these findings suggest that the upregulation of Snail expression induced by H. pylori and transformation to a spindle-like shape as a consequence in gastric cancer cells are attributable to ROS-mediated activation of Erk and the inhibition of GSK-3β signaling. © 2016 Wiley Periodicals, Inc.

  1. Effects of anti-ulcer agents on ethanol-induced gastric mucosal lesions in D-galactosamine-induced hepatitis rats.

    PubMed

    Taniguchi, Hiroyuki; Yomota, Eiji; Nogi, Koji; Onoda, Yuichi

    2002-01-01

    Patients with hepatic injury have an increased incidence of gastric ulcers and erosions. In this study, the effect of D-galactosamine(GalN)-induced hepatitis on ethanol-induced gastric mucosal lesions and the protective effect of anti-ulcer agents in rats were examined. Subcutaneous injection of GalN (1 g/kg) remarkably increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities suggesting induction of hepatic injury. Gastric mucosal lesions induced by ethanol were significantly aggravated in GalN-induced hepatitis rats. Orally administered ecabet (CAS 86408-72-2; 20-200 mg/kg) dose dependently inhibited ethanol-induced gastric mucosal lesions in GalN-induced hepatitis rats. Sucralfate (CAS 54182-58-0) tended to inhibit the gastric mucosal lesions at a dose of 200 mg/kg but teprenone (CAS 6809-52-5), cimetidine (CAS 51481-61-9) and rebamipide (CAS 90098-04-7) had little effect. All anti-ulcer agents had no effect on the serum ALT and AST activities increased by GalN pretreatment. These results indicate that the gastric mucosa of GalN-induced hepatitis rats is more susceptible to injury induced by luminal irritants such as ethanol. Ecabet potently inhibited gastric mucosal lesions suggesting its clinical utility for the gastric mucosal damage in patients with hepatic injury.

  2. Oxidative DNA damage is a preliminary step during rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide.

    PubMed

    Miranda, Sandra Regina; Noguti, Juliana; Carvalho, Juliana Gonçalves; Oshima, Celina Tijuko Fujiyama; Ribeiro, Daniel Araki

    2011-04-01

    The aim of this study was to investigate oxidative DNA damage during 4-nitroquinoline 1-oxide (4NQO)-induced rat tongue carcinogenesis. For this purpose, male Wistar rats were distributed into three groups of 10 animals each and treated with 50 ppm 4NQO solution through their drinking water for 4, 12, and 20 weeks. Ten animals were used as negative control. The alkaline Comet assay modified with lesion-specific enzymes was used to detect single and double strand breaks, labile sites (SBs), and oxidised purines and pyrimidines. Although no histopathological abnormalities were induced in the epithelium after 4 weeks of carcinogen exposure, oxidative DNA damage was detected in the 'normal' oral epithelium. In pre-neoplastic lesions and squamous cell carcinomas induced after 12 and 20 weeks following carcinogen exposure, respectively, oxidative DNA damage was also increased (P < 0.05) when compared to negative control. In conclusion, our results suggest that oxidative DNA damage is an early event during multistep carcinogenesis assay induced by 4NQO. This kind of approach should be considered to persons with high risk of oral cancer, such as in smokers or alcohol consumers.

  3. Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFκB signaling pathway in gastric cancer cells.

    PubMed

    Hsieh, Yung-Yu; Shen, Chien-Heng; Huang, Wen-Shih; Chin, Chih-Chien; Kuo, Yi-Hung; Hsieh, Meng Chiao; Yu, Hong-Ren; Chang, Te-Sheng; Lin, Tseng-Hsi; Chiu, Yung-Wei; Chen, Cheng-Nan; Kuo, Hsing-Chun; Tung, Shui-Yi

    2014-06-14

    Stromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells. Human gastric cancer cell lines were exposed to doses of resistin; SDF-1 expression and secretion levels were then determined. Real-time polymerase chain reaction and western blotting analyses were performed to clarify molecular changes. Inhibition of Toll-like receptor 4 (TLR4) by a competitive antagonist inhibited resistin-induced SDF-1 expression. Pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that activation of the p38 mitogen-activated protein kinase (MAPK) pathway is critical for resistin-induced SDF-1 expression mediated by TLR4. The promoter activity and transcription factor enzyme-linked immunosorbent assay revealed that resistin induced expression of SDF-1 mediated by NF-κB in gastric cancer cells. Inhibition of p38 MARK activation blocked the SDF-1-induced expression and the SDF-1 promoter activity in the cancer gastric cells. Chromatin immunoprecipitation assay revealed that inhibition of p38 MARK activation also blocked the resistin-increased NF-κB-DNA-binding activity. Resistin-induced SDF-1 upregulation by activation of TLR4, p38 MARK and NF-κB may explain a new role of resistin in the link of obesity and gastric cancer.

  4. Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFκB signaling pathway in gastric cancer cells

    PubMed Central

    2014-01-01

    Background Stromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells. Results Human gastric cancer cell lines were exposed to doses of resistin; SDF-1 expression and secretion levels were then determined. Real-time polymerase chain reaction and western blotting analyses were performed to clarify molecular changes. Inhibition of Toll-like receptor 4 (TLR4) by a competitive antagonist inhibited resistin-induced SDF-1 expression. Pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that activation of the p38 mitogen-activated protein kinase (MAPK) pathway is critical for resistin-induced SDF-1 expression mediated by TLR4. The promoter activity and transcription factor enzyme-linked immunosorbent assay revealed that resistin induced expression of SDF-1 mediated by NF-κB in gastric cancer cells. Inhibition of p38 MARK activation blocked the SDF-1-induced expression and the SDF-1 promoter activity in the cancer gastric cells. Chromatin immunoprecipitation assay revealed that inhibition of p38 MARK activation also blocked the resistin-increased NF-κB-DNA-binding activity. Conclusions Resistin-induced SDF-1 upregulation by activation of TLR4, p38 MARK and NF-κB may explain a new role of resistin in the link of obesity and gastric cancer. PMID:24929539

  5. Role of zinc in modulating histo-architectural and biochemical alterations during dimethylhydrazine (DMH)-induced rat colon carcinogenesis.

    PubMed

    Malhotra, Anshoo; Chadha, Vijayta Dani; Nair, Praveen; Dhawan, Devinder K

    2009-01-01

    The aim of the present work was to gain insight into the putative anticancer effect of dietary zinc during 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis. The rats were segregated into four groups, namely, normal control, DMH-treated, zinc-treated, and (DMH + zinc)-treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 12 weeks. Zinc in the form of zinc sulfate was supplemented to rats at a dose level of 227 mg/L in drinking water, ad libitum for the entire duration of the study. The effects of different treatments were studied on lipid peroxidation (LPO), reduced glutathione (GSH), and antioxidative enzymes, which included superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR), as well as on the histoarchitecture of the colon. A total of 12 weeks of DMH treatment resulted in a significant increase in LPO. GSH levels and the activities of SOD, CAT, and GST were found to be significantly decreased following DMH treatment. A significant elevation in the activity of GR was observed following 12 weeks of DMH treatment. Histopathological studies showed well-differentiated signs of dysplasia, which included nuclei enlargement, epithelial thickening, and nuclear pleomorphism indicative of promotional phase of colon carcinogenesis in DMH-administered rats. Administration of zinc to DMH-treated rats decreased the levels of LPO and GSH significantly, but the activities of SOD and CAT were found to be significantly increased following zinc treatment. Zinc supplementation along with DMH treatment did not reveal any significant change in the activity of GR but significantly improved the activity of GST, which was depressed following DMH treatment. Also, zinc treatment in DMH-treated rats showed signs of great improvement, but structureless masses of the cells and hyperchromic nuclei were still visible occasionally. In conclusion, the results of this study

  6. Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis

    PubMed Central

    Shim, Grace; Ricoul, Michelle; Hempel, William M.; Azzam, Edouard I.; Sabatier, Laure

    2014-01-01

    It is well established that ionizing radiation induces chromosomal damage, both following direct radiation exposure and via non-targeted (bystander) effects, activating DNA damage repair pathways, of which the proteins are closely linked to telomeric proteins and telomere maintenance. Long-term propagation of this radiation-induced chromosomal damage during cell proliferation results in chromosomal instability. Many studies have shown the link between radiation exposure and radiation-induced changes in oxidative stress and DNA damage repair in both targeted and non-targeted cells. However, the effect of these factors on telomeres, long established as guardians of the genome, still remains to be clarified. In this review, we will focus on what is known about how telomeres are affected by exposure to low- and high-LET ionizing radiation and during proliferation, and will discuss how telomeres may be a key player in the process of radiation-induced carcinogenesis. PMID:24486376

  7. AKT plays a crucial role in gastric cancer

    PubMed Central

    SASAKI, TAKAMITSU; YAMASHITA, YUICHI; KUNIYASU, HIROKI

    2015-01-01

    The AKT protein is involved in the phosphatidylinositol-3 kinase signaling pathway and is a vital regulator of survival, proliferation and differentiation in various types of cells. Helicobacter pylori infection induces epithelial cell proliferation and oxidative stress in chronic gastritis. These alterations lead to telomere shortening, resulting in the activation of telomerase. AKT, in particular, is activated by H. pylori-induced inflammation. AKT then promotes the expression of human telomerase reverse transcriptase, which encodes a catalytic subunit of telomerase, and induces telomerase activity, an essential component of the process of carcinogenesis. AKT activation is increased in gastric mucosa with carcinogenic properties and is associated with the low survival of patients with gastric cancer. The findings of the present study suggest that AKT is pivotal in gastric carcinogenesis and progression. PMID:26622541

  8. Protective effects of escin against indomethacin-induced gastric ulcer in mice.

    PubMed

    Wang, Tian; Zhao, Shanshan; Wang, Yucun; Yang, Yujiao; Yao, Le; Chu, Liuxiang; Du, Hanhan; Fu, Fenghua

    2014-12-01

    Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, is reported to have a potent antiulcer activity against ethanol-induced gastric mucosal lesions. This study investigated the possible mechanisms underlying the gastroprotective effect of escin against indomethacin-induced gastric ulcer in mice. Gastric ulceration was induced by a single intragastric administration of indomethacin (18 mg/kg). The mice underwent intragastric treatment with escin at doses of 0.45, 0.9 or 1.8 mg/kg. Gastric lesion was estimated morphometrically and histopathologically 6 h after the indomethacin administration. The antioxidative parameters in gastric mucosa were measured. Moreover, the activity of myeloperoxidase and the contents of TNF-α, P-selectin and VCAM-1 in gastric tissues were determined. The results showed that escin protected gastric tissues against indomethacin-induced gastropathy as demonstrated from a reduction in the ulcer index and an attenuation of histopathologic changes. Escin caused significant reductions of the contents of malondialdehyde, TNF-α, P-selectin, VCAM-1 and myeloperoxidase activity. The altered activities of superoxide dismutase, catalase and glutathione peroxidase in the stomach tissues were also ameliorated by escin treatment. The present study demonstrated that escin had a protective effect against indomethacin-induced gastric ulcer in mice, not only by virtue of its antioxidant potential, but also due to its anti-inflammatory effect.

  9. Grape seed proanthocyanidin suppression of breast cell carcinogenesis induced by chronic exposure to combined 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene.

    PubMed

    Song, Xiaoyu; Siriwardhana, Nalin; Rathore, Kusum; Lin, Degui; Wang, Hwa-Chain Robert

    2010-05-01

    Breast cancer is the most common type of cancer among women in northern America and northern Europe; dietary prevention is a cost-efficient strategy to reduce the risk of this disease. To identify dietary components for the prevention of human breast cancer associated with long-term exposure to environmental carcinogens, we studied the activity of grape seed proanthocyanidin extract (GSPE) in suppression of cellular carcinogenesis induced by repeated exposures to low doses of environmental carcinogens. We used combined carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P), at picomolar concentrations, to repeatedly treat noncancerous, human breast epithelial MCF10A cells to induce cellular acquisition of cancer-related properties of reduced dependence on growth factors, anchorage-independent growth, and acinar-conformational disruption. Using these properties as biological target endpoints, we verified the ability of GSPE to suppress combined NNK- and B[a]P-induced precancerous cellular carcinogenesis and identified the minimal, noncytotoxic concentration of GSPE required for suppressing precancerous cellular carcinogenesis. We also identified that hydroxysteroid-11-beta-dehydrogenase 2 (HSD11B2) may play a role in NNK- and B[a]P-induced precancerous cellular carcinogenesis, and its expression may act as a molecular target endpoint in GSPE's suppression of precancerous cellular carcinogenesis. And, the ability of GSPE to reduce gene expression of cytochrome-P450 enzymes CYP1A1 and CYP1B1, which can bioactivate NNK and B[a]P, possibly contributes to the preventive mechanism for GSPE in suppression of precancerous cellular carcinogenesis. Our model system with biological and molecular target endpoints verified the value of GSPE for the prevention of human breast cell carcinogenesis induced by repeated exposures to low doses of multiple environmental carcinogens. (c) 2010 Wiley-Liss, Inc.

  10. Prevention of chemically induced two-stage skin carcinogenesis in mice by systemic effects of ultraviolet irradiation.

    PubMed

    Gensler, H L

    1988-05-01

    Systemic effects of UVB irradiation (280 to 320 nm) have been shown to enhance subsequent carcinogenesis induced by UV irradiation or by high doses of benzo[a]pyrene. In the present study, we asked whether the systemic effects of UVB irradiation would influence subsequent chemical tumorigenesis induced by the initiation-promotion protocol. A group of B6D2F1/J mice were irradiated dorsally with five 30-min treatments per week for 11.5 weeks. The irradiation source was a bank of six unfiltered Westinghouse FS40 sun lamps. One week later, irradiated and unirradiated mice were initiated ventrally with 100 micrograms of 7,12-dimethylbenz[a]anthracene. Four days later, ventral 12-O-tetradecanoylphorbol-13-acetate treatments were begun. After 20 weeks of promotion, there were 75% fewer tumors per mouse in the irradiated mice than in unirradiated mice. Thus, systemic effects of UVB irradiation resulted in inhibition of chemical carcinogenesis induced with an initiation-promotion protocol.

  11. Antioxidant and antitumor efficacy of Luteolin, a dietary flavone on benzo(a)pyrene-induced experimental lung carcinogenesis.

    PubMed

    Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Barua, Chandana C; Gogoi, Ranadeep

    2016-08-01

    The present study is designed to assess the antioxidant and antitumor potential of luteolin against benzo(a)pyrene [B(a)P]-induced lung carcinogenesis in Swiss albino mice. Here, we reported that oral administration of B(a)P (50mg/kg body weight) to mice resulted in raised lipid peroxides (LPO), lung specific tumor markers such as carcinoembryonic antigen (CEA) and neuron specific enolase (NSE) with concomitant decrease in the levels of both enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx) and glutathione-s-transferase (GST), and non-enzymatic antioxidants such as reduced glutathione (GSH), vitamin E and vitamin C. Luteolin treatment (15mg/kg body weight, p.o) significantly counteracted all these alterations and maintained cellular normalcy. Moreover, assessment of protein expression levels by western blot analysis revealed that luteolin treatment effectively negates B(a)P-induced upregulated expression of proliferating cell nuclear antigen (PCNA), cytochrome P450 1A1 (CYP1A1) and nuclear factor-kappa B (NF-κB). Furthermore, histopathology of lung tissue and immunohistochemistry of CYP1A1 were carried out to substantiate the anti- lung cancer effect of luteolin. Overall, these findings confirm the chemopreventive potential of luteolin against B(a)P induced lung carcinogenesis.

  12. Chemopreventive potential of fungal taxol against 7, 12-dimethylbenz[a]anthracene induced mammary gland carcinogenesis in Sprague Dawley rats.

    PubMed

    Gokul Raj, Kathamuthu; Chidambaram, Ranganathan; Varunkumar, Krishnamoorthy; Ravikumar, Vilwanathan; Pandi, Mohan

    2015-11-15

    Breast cancer is the second most prevalent cancer and foremost global public health problem. The present study was designed to appraise the chemopreventive potential of fungal taxol against 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland carcinogenesis in Sprague Dawley rats. After 90 days of tumor induction, fungal and authentic taxol were given intraperitoneally once in a week for four weeks. Infrared thermal imaging analysis, serum biochemical parameters such as lipid peroxidase (LPO), creatinine, enzymic and non enzymic antioxidants, liver markers tests such as alanine transaminase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglycerides (TG) and lipoproteins was analysed. In addition, histopathological observation (breast, kidney and liver), immunohistochemical analysis (p53 and Her2/neu) and western blotting experiments (bcl-2, bax and caspase-9) were performed both in control and experimental animals. In thermal imaging, decreased temperature was observed in rat treated with fungal and authentic taxol when compared to tumor induced rats. The significant decrease in LPO, creatinine, ALT, AST, TC, TG, lipoproteins and increase in enzymic, non-enzymic antioxidants were exemplified in serum of treated groups. Further histopathology, immunohistochemical and western blot analysis (bax, cas-9 and bcl-2) of apoptotic markers in breast tissues clearly showed the anti-carcinogenic property of fungal taxol. Our findings implement that fungal taxol is a potential chemo preventive agent against DMBA induced mammary gland carcinogenesis. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Effect of Cissus quadrangularis on gastric mucosal defensive factors in experimentally induced gastric ulcer-a comparative study with sucralfate.

    PubMed

    Jainu, Mallika; Devi, C S Shyamala

    2004-01-01

    Cissus quadrangularis is an indigenous plant commonly mentioned in Ayurveda for treatment of gastric ulcers. The ulcer-protective effect of a methanolic extract of C. quadrangularis (CQE) was comparable to that of the reference drug sucralfate. Further, gastric juice and mucosal studies showed that CQE at a dose of 500 mg/kg given for 10 days significantly increased the mucosal defensive factors like mucin secretion, mucosal cell proliferation, glycoproteins, and life span of cells. The present investigation suggests that CQE not only strengthens mucosal resistance against ulcerogens but also promotes healing by inducing cellular proliferation. Thus, CQE has potential usefulness for treatment of peptic ulcer disease.

  14. Morphological and Molecular Alterations in 1,2 Dimethylhydrazine and Azoxymethane Induced Colon Carcinogenesis in Rats

    PubMed Central

    Perše, Martina; Cerar, Anton

    2011-01-01

    The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many morphological as well as molecular similarities to human sporadic colorectal cancer (CC), which are summarized and discussed in this paper. In addition, the paper combines present knowledge of morphological and molecular features in the multistep development of CC recognized in the DMH/AOM rat model. This understanding is necessary in order to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH/AOM rat colon carcinogenesis. The DMH/AOM model provides a wide range of options for investigating various initiating and environmental factors, the role of specific dietary and genetic factors, and therapeutic options in CC. The limitations of this model and suggested areas in which more research is required are also discussed. PMID:21253581

  15. Cytochrome P450 2E1 inhibition prevents hepatic carcinogenesis induced by diethylnitrosamine in alcohol-fed rats

    PubMed Central

    Ye, Qinyuan; Lian, Fuzhi; Chavez, Pollyanna R.G.; Chung, Jayong; Ling, Wenhua; Qin, Hua; Seitz, Helmut K.

    2012-01-01

    Chronic alcohol ingestion increases hepatic cytochrome P450 2E1 (CYP2E1), which is associated with hepatocarcinogenesis. We investigated whether treatment with chlormethiazole (CMZ), a CYP2E1 inhibitor, protects against alcohol-associated hepatic carcinogenesis in rats. Rats were fed either an ethanol liquid diet or a non-ethanol liquid diet, with or without CMZ for one and ten months. A single intraperitoneal injection of diethylnitrosamine (DEN, 20 mg/kg) was given to initiate hepatic carcinogenesis. CYP2E1 expression, inflammatory proteins, cell proliferation, protein-bound 4-HNE, etheno-DNA adducts, 8-hydroxy-2'-deoxyguanosine (8-OHdG), retinoid concentrations, and hepatic carcinogenesis were examined. Ethanol feeding for 1 month with DEN resulted in significantly increased hepatic CYP2E1 levels and increased nuclear accumulation of NF-κB protein and TNF-α expression, which were associated with increased cyclin D1 expression and p-GST positive altered hepatic foci. All of these changes induced by ethanol feeding were significantly inhibited by the one month CMZ treatment. At 10-months of treatment, hepatocellular adenomas were detected in ethanol-fed rats only, but neither in control rats nor in animals receiving ethanol and CMZ. The 8-OHdG formation was found to be significantly increased in ethanol fed animals and normalized with CMZ treatment. In addition, alcohol-reduced hepatic retinol and retinoic acid concentrations were restored by CMZ treatment to normal levels in the rats at 10 months of treatment. These data demonstrate that the inhibition of ethanol-induced CYP2E1 as a key pathogenic factor can counteract the tumor-promoting action of ethanol by decreasing TNF-α expression, NF-κB activation, and oxidative DNA damage as well as restoring normal hepatic levels of retinoic acid in DEN-treated rats. PMID:23543859

  16. Prevention of azoxymethane/dextran sodium sulfate-induced mouse colon carcinogenesis by processed Aloe vera gel.

    PubMed

    Im, Sun-A; Kim, Ji-Wan; Kim, Hee-Suk; Park, Chan-Su; Shin, Eunju; Do, Seon-Gil; Park, Young In; Lee, Chong-Kil

    2016-11-01

    The preventive effect of a processed Aloe vera gel (PAG) on colon carcinogenesis was examined using an azoxymethane (AOM)-initiated and dextran sodium sulfate (DSS)-promoted mouse colon carcinogenesis model. Oral administration of PAG (200, or 400mg/kg/day) significantly reduced the multiplicity of colonic adenomas and adenocarcinomas compared with the AOM/DSS only-treated mice. In the mice treated with 400mg/kg of PAG, adenoma and adenocarcinoma development was reduced to 80% and 60%, respectively, compared to 100% in the PAG-untreated AOM/DSS-treated mice. Western blot analysis using colon extracts showed that PAG reduced the activation of nuclear factor kappa B (NF-κB), resulting in the inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression. PAG appeared to inhibit the NF-κB activation through the activation of peroxisome proliferator-activated receptor gamma. PAG also inhibited the expression and phosphorylation of signal transducer and activator of transcription 3, which is known to connect inflammation and cancer. In addition, PAG inhibited cell cycle progression-inducing cellular factors, such as extracellular signal-regulated kinases 1/2, cyclin-dependent kinase 4, and cyclin D1. On the other hand, PAG increased the expression of Caudal-related homeobox transcription factor 2, which is known to be a tumor suppressor in colorectal cancer. These findings show that PAG suppresses colitis-related colon carcinogenesis by inhibiting both chronic inflammation and cell cycle progression in the colon. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Effect of teprenone on gastric mucosal injury induced by Helicobacter pylori in rats.

    PubMed

    Saita, H; Murakami, M

    2000-12-01

    The aim of this study was to investigate the protective effect of gastric mucus against Helicobacter pylori-induced gastric mucosal injury, measuring intramucosal mucus and the surface hydrophobicity. Male Sprague-Dawley rats' stomachs were exposed to H. pylori suspension (1 x 10(5) ml) plus 1 ml of urea solution (400 mg/dl) with gastric ischemia (withdrawal of 3 ml of blood) for 60 min, 60 min after pretreatment with teprenone (CAS 6809-52-5) (50 mg/rat, intragastric). The control rats were treated in the same manner without pretreatment with teprenone. A high concentration of intragastric ammonia was generated 60 min after administration of H. pylori plus urea in both the control and the teprenone-pretreated rats. A reduction in transmucosal potential difference, formation of hemorrhagic gastric lesions, and impairment in both intramucosal mucus and surface hydrophobicity were observed in the corpus of the control rats. However, the pretreatment with teprenone prevented such a reduction in potential difference and the development of gastric lesions against ammonia through the preservation of gastric mucus. The preservation of gastric mucus might protect gastric mucosa against attacks by H. pylori, suggesting that the mechanism of H. pylori-associated gastric injury is associated with the decrease in gastric mucus.

  18. Changes in polyamine levels and protein synthesis rate during rat liver carcinogenesis induced by 4-dimethylaminoazobenzene.

    PubMed

    Perin, A; Sessa, A

    1978-01-01

    The concentrations of putrescine, spermidine, and spermine in liver of rats fed on 4-dimethylaminoazobenzene and in the resultant hepatomas were found to be significantly higher than were those observed in normal liver from rats of the same strain, sex, and age. These modifications were due to the carcinogen and not to the special low-riboflavin diet used to obtain the carcinogenic effect of 4-dimethylaminoazobenzene. The first change observed during liver carcinogenesis was the early increase in the putrescine level, followed by an increase of spermidine and spermine, which reached maximum levels in growing hepatomas. A significant increase of urinary polyamines was also observed in tumor-bearing rats. Experiments on leucine incorporation into proteins of tissue slices, which were obtained from the same tissues on which polyamine determinations were carried out, showed that in rat liver carcinogenesis the rate of protein synthesis was well correlated with the polyamine levels. These results suggest that polyamines may play a role in the process of carcinogenesis and in tumor protein synthesis in vivo.

  19. Participation of microbiota in the development of gastric cancer

    PubMed Central

    Wang, Li-Li; Yu, Xin-Juan; Zhan, Shu-Hui; Jia, Sheng-Jiao; Tian, Zi-Bin; Dong, Quan-Jiang

    2014-01-01

    There are a large number of bacteria inhabiting the human body, which provide benefits for the health. Alterations of microbiota participate in the pathogenesis of diseases. The gastric microbiota consists of bacteria from seven to eleven phyla, predominantly Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria and Fusobacteria. Intrusion by Helicobacter pylori (H. pylori) does not remarkably interrupt the composition and structure of the gastric microbiota. Absence of bacterial commensal from the stomach delays the onset of H. pylori-induced gastric cancer, while presence of artificial microbiota accelerates the carcinogenesis. Altered gastric microbiota may increase the production of N-nitroso compounds, promoting the development of gastric cancer. Further investigation of the carcinogenic mechanisms of microbiota would benefit for the prevention and management of gastric cancer. PMID:24803806

  20. Participation of microbiota in the development of gastric cancer.

    PubMed

    Wang, Li-Li; Yu, Xin-Juan; Zhan, Shu-Hui; Jia, Sheng-Jiao; Tian, Zi-Bin; Dong, Quan-Jiang

    2014-05-07

    There are a large number of bacteria inhabiting the human body, which provide benefits for the health. Alterations of microbiota participate in the pathogenesis of diseases. The gastric microbiota consists of bacteria from seven to eleven phyla, predominantly Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria and Fusobacteria. Intrusion by Helicobacter pylori (H. pylori) does not remarkably interrupt the composition and structure of the gastric microbiota. Absence of bacterial commensal from the stomach delays the onset of H. pylori-induced gastric cancer, while presence of artificial microbiota accelerates the carcinogenesis. Altered gastric microbiota may increase the production of N-nitroso compounds, promoting the development of gastric cancer. Further investigation of the carcinogenic mechanisms of microbiota would benefit for the prevention and management of gastric cancer.

  1. Docosahexaenoic acid, an omega-3 polyunsaturated acid protects against indomethacin-induced gastric injury.

    PubMed

    Pineda-Peña, Elizabeth Arlen; Jiménez-Andrade, Juan Miguel; Castañeda-Hernández, Gilberto; Chávez-Piña, Aracely Evangelina

    2012-12-15

    Previous studies have shown gastroprotective effect of fish oil in several experimental models. However, the mechanisms and active compounds underlying this effect are not fully understood. Fish oil has several components; among them, one of the most studied is docosahexaenoic acid (DHA), which is an omega-3 long-chain polyunsaturated fatty acid. The aim of this study was to examine the gastroprotective effect of DHA as a pure compound in a rat model of indomethacin-induced gastric injury as well as elucidate some of the mechanism(s) behind DHA's gastroprotective effect. Indomethacin was orally administered to induce an acute gastric injury (3, 10 and 30mg/kg). Omeprazol (a proton pump inhibitor, 30mg/kg, p.o.) and DHA (3, 10, 30mg/kg, p.o.) were gavaged 30 and 120min, respectively, before indomethacin insult (30mg/kg p.o.). Three hours after indomethacin administration, rats were sacrificed, gastric injury was evaluated by determining the total damaged area. A sample of gastric tissue was harvested and processed to quantify prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) levels by enzyme-linked immunosorbent assay. Indomethacin produced gastric injury in dose-dependent manner. DHA protected against indomethacin-induced gastric damage, and this effect was comparable with omeprazol's gastroprotective effect. DHA did not reverse the indomethacin-induced reduction of PGE(2) gastric levels. In contrast, DHA partially prevented the indomethacin-induced increase in LTB(4) gastric levels. This is the first report demonstrating DHA's gastroprotective effect as a pure compound. Furthermore, the results reveal that the gastroprotective effect is mediated by a decrease in gastric LTB(4) levels in indomethacin-induced gastric damage.

  2. Effects of long term feeding of raw soya bean flour on virus-induced pancreatic carcinogenesis in guinea fowl.

    PubMed

    Kirev, T; Woutersen, R A; Kiril, A

    1999-01-29

    The effects of a diet enriched with 25% raw soya bean flour (RSF) on the pancreas and on the avian retrovirus Pts 56-induced pancreatic carcinogenesis in guinea fowl were studied. It has been shown that prolonged RSF feeding of new-hatched virus-infected and uninfected guinea fowl-poults induced enlargement of the pancreas, which was less pronounced when administration of the RSF supplemented diet started at the age of 75 days. Time-dependent multifocal inter- and intralobular hyperplasia of pleomorphic ducts lined by mucin-producing epithelium in the exocrine pancreas of virus-infected guinea fowls fed a RSF supplemented diet was regularly observed. Enlargement of virus-induced ductular neoplasms has been shown only after simultaneous RSF and virus administration.

  3. Mechanisms of curcumin-induced gastroprotection against ethanol-induced gastric mucosal lesions.

    PubMed

    Czekaj, Renata; Majka, Jolanta; Magierowska, Katarzyna; Sliwowski, Zbigniew; Magierowski, Marcin; Pajdo, Robert; Ptak-Belowska, Agata; Surmiak, Marcin; Kwiecien, Slawomir; Brzozowski, Tomasz

    2017-08-30

    Curcumin, a pleiotropic substance used for centuries in traditional medicine, exhibits antioxidant, anti-inflammatory and antiproliferative efficacy against various tumours, but the role of curcumin in gastroprotection is little studied. We determined the effect of curcumin against gastric haemorrhagic lesions induced by 75% ethanol and alterations in gastric blood flow (GBF) in rats with cyclooxygenase-1 (COX-1) and COX-2 activity inhibited by indomethacin, SC-560 or rofecoxib, inhibited NO-synthase activity, capsaicin denervation and blockade of TRPV1 receptors by capsazepine. One hour after ethanol administration, the gastric mucosal lesions were assessed by planimetry, the GBF was examined by H2 gas clearance, plasma gastrin was determined by radioimmunoassay, and the gastric mucosal mRNA expression of Cdx-2, HIF-1α, HO-1 and SOD 2 was analysed by RT-PCR. Curcumin, in a dose-dependent manner, reduced ethanol-induced gastric lesions and significantly increased GBF and plasma gastrin levels. Curcumin-induced protection was completely reversed by indomethacin and SC-560, and significantly attenuated by rofecoxib, L-NNA, capsaicin denervation and capsazepine. Curcumin downregulated Cdx-2 and Hif-1α mRNA expression and upregulated HO-1 and SOD 2, and these effects were reversed by L-NNA and further restored by co-treatment of L-NNA with L-arginine. Curcumin-induced protection against ethanol damage involves endogenous PG, NO, gastrin and CGRP released from sensory nerves due to activation of the vanilloid TRPV1 receptor. This protective effect can be attributed to the inhibition of HIF-1α and Cdx-2 expression and the activation of HO-1 and SOD 2 expression.

  4. Raman spectroscopic investigation of the chemopreventive response of naringenin and its nanoparticles in DMBA-induced oral carcinogenesis

    NASA Astrophysics Data System (ADS)

    Krishnakumar, N.; Sulfikkarali, N. K.; Manoharan, S.; Venkatachalam, P.

    2013-11-01

    Raman spectroscopy is a vibrational spectroscopic technique that can be used to optically probe the biomolecular changes associated with tumor progression. The aim of the present study is to investigate the biomolecular changes in chemopreventive response of prepared naringenin-loaded nanoparticles (NARNPs) relative to efficacy of free naringenin (NAR) during 7,12-dimethyl benz(a)anthracene (DMBA)-induced oral carcinogenesis by Fourier Transform Raman (FT-Raman) spectroscopy. Oral squamous cell carcinoma (OSCC) was developed in the buccal pouch of golden Syrian hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. Raman spectra differed significantly between the control and tumor tissues, with tumors showing higher percentage signals for nucleic acids, phenylalanine and tryptophan and a lower in the percentage of phospholipids. Moreover, oral administration of free NAR and NARNPs significantly increased phospholipids and decreased the levels of tryptophan, phenylalanine and nucleic acid contents. On a comparative basis, NARNPs was found to have a more potent antitumor effect than free NAR in completely preventing the formation of squamous cell carcinoma and in improving the biochemical status to a normal range in DMBA-induced oral carcinogenesis. The present study further suggest that Raman spectroscopy could be a valuable tool for rapid and sensitive detection of specific biomolecular changes in response to chemopreventive agents.

  5. Effect of Spirogyra neglecta on the early stages of 1, 2-dimethylhydrazine-induced colon carcinogenesis in rats.

    PubMed

    Taya, Sirinya; Thumvijit, Tarika; Chewonarin, Teera; Punvittayagul, Charatda; Wongpoomchai, Rawiwan

    2016-12-06

    This study focused on the chemopreventive effects of Spirogyra neglecta extract (SNE) and dried S. neglecta mixed diet on the early stages of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats. Male Wistar rats were injected with DMH to initiate aberrant crypt foci (ACF) formation. In the initiation stage, SNE significantly decreased the number of ACF in the colon of DMH-treated rats. Rats that received a low dose of SNE showed enhanced activity of several detoxifying and antioxidant enzymes. In the postinitiation stage, a low dose of SNE significantly decreased the number of ACF in the colon of DMH-treated rats. It significantly reduced the number of proliferating cell nuclear antigen-positive cells and increased the number of apoptotic cells in colonic crypts. S. neglecta thus inhibited the development of the early stages of DMH-induced colon carcinogenesis in rats by modulation of xenobiotic metabolizing enzymes and inhibition of cell proliferation as well as induction of apoptosis.

  6. Grape juice concentrate (G8000™) modulates apoptosis but not oxidative stress following rat colon carcinogenesis induced by azoxymethane.

    PubMed

    Oshima, Celina Tizuko Fujiyama; Landman, Gilles; Paiotti, Ana Paula Ribeiro; Artigiani Neto, Ricardo; Silva, Roseane Mendes; Campanholo, Vanessa Maria De Lima Pazine; Gollucke, Andrea Pittelli Boiago; Ribeiro, Daniel Araki; Forones, Nora Manoukian

    2015-02-01

    The aim of this study was to evaluate if grape juice concentrate is able to protect against experimental colon carcinogenesis. For this purpose, a total of 35 male Wistar rats were randomly distributed into seven groups: G1: SHAM animals receiving only saline; G2: animals receiving 15 mg/kg azoxymethane (AOM); G3: animals receiving 1% grape juice concentrate 2 weeks before the administration of AOM; G4: animals receiving 2% grape juice concentrate 2 weeks before the administration of AOM; G5: animals receiving 1% grape juice concentrate 4 weeks after the last administration of AOM; G6: animals receiving 2% grape juice concentrate 4 weeks after the last administration of AOM; G7: animals receiving only 2% grape juice concentrate. The group that received 2% grape juice concentrate before induction with AOM showed the decreased expression of Bcl-2 compared to those animals that were induced by AOM (positive control). Regarding Bax, animals that received grape juice at 2% decreased Bax immunoexpression when compared to AOM group. Furthermore, animals that intake grape juice at 1% after induced by AOM decreased Bax immunoexpression as well. 8-OHdGLI did not show significant statistically differences (p > 0.05) among groups. In summary, our results demonstrate that grape juice is able to modulate rat colon carcinogenesis as a result of induction of apoptosis.

  7. Chemopreventive efficacy of green tea drinking against 1,2-dimethyl hydrazine-induced rat colon carcinogenesis.

    PubMed

    Sadik, Nermin A H

    2013-04-01

    Colorectal cancer is one of the leading causes of tumour-related deaths. In the present study, the chemopreventive effect of green tea on 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis was studied in male Wistar rats. The DMH group received subcutaneous injections of DMH (30 mg kg(-1) body weight) once a week for 30 weeks, the normal group received the vehicle of DMH, and the DMH + green tea group received DMH simultaneously with 1% green tea as their sole source of drinking fluid throughout the experimental period. In the DMH group treated with green tea, significant reductions in gene overexpressions of colonic nuclear factor κB (NF-κB), tumour necrosis factor α, inducible nitric oxide synthase and cyclooxygenase 2, and NF-κB immunostaining indicates the anti-inflammatory effect of green tea in attenuating colon cancer. Moreover, the anti-angiogenic and anti-invasiveness effects of green tea were revealed as reductions of both vascular endothelial growth factor and matrix metalloproteinase-7 mRNA expression levels. These effects were confirmed by the significant reduction of serum tumour necrosis factor α, C-reactive protein levels, inhibition of tumour incidence, and nearly normal survival rate and colonic architecture. It can be concluded that green tea exerts a potent chemopreventive effect on colon carcinogenesis possibly due to the inhibition of NF-κB.

  8. Gastroprotective potentials of the ethanolic extract of Mukia maderaspatana against indomethacin-induced gastric ulcer in rats.

    PubMed

    Gomathy, G; Venkatesan, D; Palani, S

    2015-01-01

    This study investigated the protective effects of the ethanolic extract of Mukia maderaspatana against indomethacin-induced gastric ulcer in rats. Gastric ulceration was induced by single intraperitoneal injection of indomethacin (30 mg/kg b.wt.). M. maderaspatana extract produced significant reduction in gastric mucosal lesions, malondialdehyde and serum tumour necrosis factor-α associated with a significant increase in gastric juice mucin content and gastric mucosal catalase, nitric oxide and prostaglandin E2 levels. The volume and acidity of the gastric juice decreased in pretreated rats. The plant extract was evaluated in the gastric juice of rats, untreated has showed near normal levels in pretreated rats. The M. maderaspatana was able to decrease acidity and increase the mucosal defence in the gastric area, therefore justifying its use as an antiulcerogenic agent. Ranitidine significantly increased pH value and decreased pepsin activity and gastric juice free and total acidity. The anti-ulcer effect was further confirmed histologically.

  9. Chemical carcinogenesis.

    PubMed

    Oliveira, Paula A; Colaço, Aura; Chaves, Raquel; Guedes-Pinto, Henrique; De-La-Cruz P, Luis F; Lopes, Carlos

    2007-12-01

    The use of chemical compounds benefits society in a number of ways. Pesticides, for instance, enable foodstuffs to be produced in sufficient quantities to satisfy the needs of millions of people, a condition that has led to an increase in levels of life expectancy. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. There are three stages involved in chemical carcinogenesis. These are defined as initiation, promotion and progression. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair--i.e. mutations in proto-oncogenes and tumour suppressing genes. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals.

  10. Alcoholic beverages and gastric epithelial cell viability: effect on oxidative stress-induced damage.

    PubMed

    Loguercio, C; Tuccillo, C; Federico, A; Fogliano, V; Del Vecchio Blanco, C; Romano, M

    2009-12-01

    Alcohol is known to cause damage to the gastric epithelium independently of gastric acid secretion. Different alcoholic beverages exert different damaging effects in the stomach. However, this has not been systematically evaluated. Moreover, it is not known whether the non-alcoholic components of alcoholic beverages also play a role in the pathogenesis of gastric epithelial cell damage. Therefore, this study was designed to evaluate whether different alcoholic beverages, at a similar ethanol concentration, exerted different damaging effect in gastric epithelial cells in vitro. Moreover, we evaluated whether pre-treatment of gastric epithelial cells with alcoholic beverages prevented oxidative stress-induced damage to gastric cells. Cell damage was assessed, in MKN-28 gastric epithelial cells, by MTT assay. Oxidative stress was induced by incubating cells with xanthine and xanthine oxidase. Gastric cell viability was assessed following 30, 60, and 120 minutes incubation with ethanol 17.5-125 mg/ml(-1) or different alcoholic beverages (i.e., beer, white wine, red wine, spirits) at comparable ethanol concentration. Finally, we assessed whether pre-incubation with red wine (with or without ethanol) prevented oxidative stress-induced cell damage. Red wine caused less damage to gastric epithelial cells in vitro compared with other alcoholic beverages at comparable ethanol concentration. Pre-treatment with red wine, but not with dealcoholate red wine, significantly and time-dependently prevented oxidative stress-induced cell damage. 1) red wine is less harmful to gastric epithelial cells than other alcoholic beverages; 2) this seems related to the non-alcoholic components of red wine, because other alcoholic beverages with comparable ethanol concentration exerted more damage than red wine; 3) red wine prevents oxidative stress-induced cell damage and this seems to be related to its ethanol content.

  11. Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models

    PubMed Central

    Williams, Jonathan M.

    2017-01-01

    ABSTRACT Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems. PMID:28151409

  12. Resveratrol enhances cell-mediated immune response to DMBA through TLR4 and prevents DMBA induced cutaneous carcinogenesis

    PubMed Central

    Yusuf, Nabiha; Nasti, Tahseen H; Meleth, Sreelatha; Elmets, Craig A

    2009-01-01

    Toll like receptors (TLRs) activate signals that are critically involved in innate immune responses and that contribute to the initiation of adaptive immune responses. Resveratrol (trans-3, 5,4-trihydroxystilbene), a polyphenol found in red grapes and in several other plant sources, is an effective chemopreventive agent in cutaneous chemical carcinogenesis. In this study, we investigated whether TLR4 was required for the chemopreventive action of resveratrol in DMBA skin carcinogenesis. For this purpose, mice with normal and deficient TLR4 function were compared when pretreated with resveratrol and then subjected to a DMBA-induced skin carcinogenesis protocol. There were fewer tumors/group (p<0.001) in resveratrol treated TLR4 competent C3H/HeN mice than in TLR4 deficient C3H/HeJ mice. In addition, the size of tumors in C3H/HeN mice was reduced in vivo and their survival in vitro was inhibited by resveratrol to a significantly greater extent than in C3H/HeJ mice. Resveratrol inhibited angiogenesis to a much greater extent in the TLR4 competent mice than in TLR4 deficient mice. IFN-γ and IL-12 levels were also increased in TLR4 competent mice compared to TLR4 deficient mice, and TLR4 competent C3H/HeN mice exhibited a greater increase in the cell-mediated immune response to DMBA. The results of this study indicate that TLR4 is an important mediator of resveratrol chemoprevention in DMBA skin tumorigenesis. PMID:19142898

  13. Effects of selenium on 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis and DNA adduct formation

    SciTech Connect

    Ip, C.; Daniel, F.B.

    1985-01-01

    The purpose of the present investigation was to determine the effects of dietary selenium deficiency or excess on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary neoplasia in rats and to delineate whether selenium-mediated modification of mammary carcinogenesis was associated with changes in carcinogen:DNA adduct formation and activities of liver microsomal enzymes that are involved in xenobiotic metabolism. Female Sprague-Dawley rats were divided into three groups from weaning and were maintained on one of three synthetic diets designated as follows: selenium deficient (less than 0.02 ppm); selenium adequate (0.2 ppm); or selenium excess (2.5 ppm). For the DMBA binding and DNA adduct studies, rats were given a dose of (/sup 3/H)DMBA p.o. after 1 month on their respective diets. Results from the liver and the mammary gland indicated that neither selenium deficiency nor excess had any significant effect on the binding levels, which were calculated on the basis of total radioactivity isolated with the purified DNA. Furthermore, it was found that dietary selenium intake did not seem to affect quantitatively or qualitatively the formation of DMBA:DNA adducts in the liver. Similarly, in a parallel group of rats that did not receive DMBA, the activities of aniline hydroxylase, aminopyrine N-demethylase, and cytochrome c reductase were not significantly altered by dietary selenium levels. Concurrent with the above experiments, the effect of dietary selenium intake on carcinogenesis was also monitored. Results of this experiment indicated that selenium deficiency enhanced mammary carcinogenesis only when this nutritional condition was maintained in the postinitiation phase. Likewise, an excess of selenium intake inhibited neoplastic development only when this regimen was continued after DMBA administration.

  14. Role of Innate Immunity in Helicobacter pylori-Induced Gastric Malignancy

    PubMed Central

    Peek, Richard M.; Fiske, Chris; Wilson, Keith T.

    2010-01-01

    Helicobacter pylori colonizes the majority of persons worldwide, and the ensuing gastric inflammatory response is the strongest singular risk factor for peptic ulceration and gastric cancer. However, only a fraction of colonized individuals ever develop clinically significant outcomes. Disease risk is combinatorial and can be modified by bacterial factors, host responses, and/or specific interactions between host and microbe. Several H. pylori constituents that are required for colonization or virulence have been identified, and their ability to manipulate the host innate immune response will be the focus of this review. Identification of bacterial and host mediators that augment disease risk has profound ramifications for both biomedical researchers and clinicians as such findings will not only provide mechanistic insights into inflammatory carcinogenesis but may also serve to identify high-risk populations of H. pylori-infected individuals who can then be targeted for therapeutic intervention. PMID:20664074

  15. Role of endogenous gastric mucosal prostaglandins in the formation of acute gastric mucosal lesions induced by aspirin, ethanol, HCl and CH3COOH.

    PubMed

    Amioka, I; Arima, T; Nagashima, H

    1987-06-01

    The role of endogenous mucosal prostaglandins (PGs) in the production of acute gastric mucosal lesions (AGML) was examined in rats. Aspirin, ethanol or 0.6 N-HCl was given intragastrically and 20% acetic acid was injected into the gastric wall. Endogenous gastric mucosal PG (A + B), PGE and PGF were determined by radioimmunoassay. Their gastric contents were markedly reduced by aspirin administration (p less than 0.001). The level of gastric mucosal PGs still remained low (p less than 0.001) after the aspirin-induced AGML began to heal. Furthermore, rats with AGML induced by ethanol, HCl or acetic acid, showed no decrease in endogenous gastric mucosal PGs compared with the controls. These findings indicated that endogenous PGs are not necessary for either the induction or healing of experimental AGML.

  16. Centella asiatica Leaf Extract Protects Against Indomethacin-Induced Gastric Mucosal Injury in Rats.

    PubMed

    Zheng, Hong-Mei; Choi, Myung-Joo; Kim, Jae Min; Cha, Kyung Hoi; Lee, Kye Wan; Park, Yu Hwa; Hong, Soon-Sun; Lee, Don Haeng

    2016-01-01

    The present study evaluated the protective effect of Centella asiatica (gotu kola) leaf extract (CAE) against indomethacin (IND)-induced gastric mucosal injury in rats. Gastric mucosal injury was induced by the oral administration of IND to the rats after a 24 h fast. CAE (50 or 250 mg/kg) or lansoprazole (a reference drug) was orally administrated 30 min before the IND administration, and 5 h later, the stomachs were removed to quantify the lesions. Orally administered CAE significantly reduced IND-induced gastric injury. The histopathological observations (hematoxylin-eosin and Periodic acid-Schiff staining) confirmed the protection against gastric mucosal injury. Also, CAE decreased the malondialdehyde content compared to the control group. Moreover, pretreatment with CAE resulted in a significant reduction in the elevated expression of tumor necrosis factor, Cyclooxygenase (COX)-2, and inducible nitric oxide synthase. These results suggested that CAE possesses gastroprotective effects against IND-induced gastric mucosal injury, which could be attributed to its ability to inhibit lipid peroxidation and stimulate gastric mucus secretion in the rat gastric mucosa.

  17. Impaired CK1 Delta Activity Attenuates SV40-Induced Cellular Transformation In Vitro and Mouse Mammary Carcinogenesis In Vivo

    PubMed Central

    Hirner, Heidrun; Günes, Cagatay; Bischof, Joachim; Wolff, Sonja; Grothey, Arnhild; Kühl, Marion; Oswald, Franz; Wegwitz, Florian; Bösl, Michael R.; Trauzold, Anna; Henne-Bruns, Doris; Peifer, Christian; Leithäuser, Frank; Deppert, Wolfgang; Knippschild, Uwe

    2012-01-01

    Simian virus 40 (SV40) is a powerful tool to study cellular transformation in vitro, as well as tumor development and progression in vivo. Various cellular kinases, among them members of the CK1 family, play an important role in modulating the transforming activity of SV40, including the transforming activity of T-Ag, the major transforming protein of SV40, itself. Here we characterized the effects of mutant CK1δ variants with impaired kinase activity on SV40-induced cell transformation in vitro, and on SV40-induced mammary carcinogenesis in vivo in a transgenic/bi-transgenic mouse model. CK1δ mutants exhibited a reduced kinase activity compared to wtCK1δ in in vitro kinase assays. Molecular modeling studies suggested that mutation N172D, located within the substrate binding region, is mainly responsible for impaired mutCK1δ activity. When stably over-expressed in maximal transformed SV-52 cells, CK1δ mutants induced reversion to a minimal transformed phenotype by dominant-negative interference with endogenous wtCK1δ. To characterize the effects of CK1δ on SV40-induced mammary carcinogenesis, we generated transgenic mice expressing mutant CK1δ under the control of the whey acidic protein (WAP) gene promoter, and crossed them with SV40 transgenic WAP-T-antigen (WAP-T) mice. Both WAP-T mice as well as WAP-mutCK1δ/WAP-T bi-transgenic mice developed breast cancer. However, tumor incidence was lower and life span was significantly longer in WAP-mutCK1δ/WAP-T bi-transgenic animals. The reduced CK1δ activity did not affect early lesion formation during tumorigenesis, suggesting that impaired CK1δ activity reduces the probability for outgrowth of in situ carcinomas to invasive carcinomas. The different tumorigenic potential of SV40 in WAP-T and WAP-mutCK1δ/WAP-T tumors was also reflected by a significantly different expression of various genes known to be involved in tumor progression, specifically of those involved in wnt-signaling and DNA repair. Our data

  18. Gastroprotective effect of gamma-aminobutyric acid against ethanol-induced gastric mucosal injury.

    PubMed

    Xie, Min; Chen, Haihong; Nie, Shaoping; Tong, Wei; Yin, Junyi; Xie, Mingyong

    2017-06-25

    The present study aimed to investigate the gastroprotective effect of gamma-aminobutyric acid (GABA) on ethanol-induced gastric mucosal injury and gastric epithelial cells injury. Rats were divided into the control group, vehicle group and GABA-treated groups (10, 20 and 40 mg/kg/day). After GABA ingestion for 14 days, rats except the control group were given 1 mL pure ethanol by oral gavage in order to induce acute gastric mucosal lesion. The human gastric epithelial cell line GES-1 was incubated with GABA (100, 200 and 400 μM) for 24 h, followed by treatment with 8% ethanol for 3 h to induce cell injury. The results showed that GABA pretreatment significantly reduced gastric ulcer index in a dose-dependent manner. GABA pretreatment could not only remarkably restrain oxidative stress by increasing activities of superoxide dismutase and catalase as well as decreasing content of malondialdehyde both in gastric tissue and cells, but also significantly reduced pro-inflammatory factors (interleukin-6 and tumor necrosis factor α) levels in gastric tissue. In addition, significant augments of prostaglandin E2 and nitric oxide levels were observed in the gastric tissues of 40 mg/kg/d GABA treated group. In conclusion, the results in this study suggested that GABA could alleviate ethanol-induced gastric mucosal injury and gastric epithelial cells injury through the improvement of anti-inflammatory and anti-oxidant status, as well as the increase of PGE2 and NO levels. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Basic Mechanics of DNA Methylation and the Unique Landscape of the DNA Methylome in Metal-Induced Carcinogenesis

    PubMed Central

    Brocato, Jason; Costa, Max

    2013-01-01

    DNA methylation plays an intricate role in the regulation of gene expression and events that compromise the integrity of the methylome may potentially contribute to disease development. DNA methylation is a reversible and regulatory modification that elicits a cascade of events leading to chromatin condensation and gene silencing. In general, normal cells are characterized by gene-specific hypomethylation and global hypermethylation, while cancer cells portray a reverse profile to this norm. The unique methylome displayed in cancer cells is induced after exposure to carcinogenic metals such as nickel, arsenic, cadmium, and chromium (VI). These metals alter the DNA methylation profile by provoking both hyper- and hypomethylation events. The metal-stimulated deviations to the methylome are possible mechanisms for metal-induced carcinogenesis and may provide potential biomarkers for cancer detection. Development of therapies based on the cancer methylome requires further research including human studies that supply results with larger impact and higher human relevance. PMID:23844698

  20. Cholera toxin, a potent inducer of epidermal hyperplasia but with no tumor promoting activity in mouse skin carcinogenesis

    SciTech Connect

    Kuroki, T.; Chida, K.; Munakata, K.; Murakami, Y.

    1986-05-29

    Intracutaneous injection of cholera toxin into mice induced epidermal hyperplasia to a greater extent than 12-O-tetra-decanoylphorbol-13-acetate. It also induced adenylate cyclase and through weakly, ornithine decarboxylase of the epidermis. Cholera toxin, however, showed no tumor promoting activity in mouse skin carcinogenesis. In the single stage promotion, cholera toxin (50 ng) was injected once a week for 10 weeks into the skin of SENCAR mice initiated with 25 ..mu..g 7,12-dimethyl-benz(a)anthracene, but no tumors developed. In the two-stage promotion test, cholera toxin (10-100 ng) was injected for one or two weeks into the initiated skin and then mezerein (4 ..mu..g) was applied twice a week for 18 weeks, but the toxin did not increase incidence or numbers of papillomas.

  1. Oral Consumption of Bitter Gourd and Tomato Prevents Lipid Peroxidation in Liver Associated with DMBA Induced Skin Carcinogenesis in Mice.

    PubMed

    De, Sarmishtha; Chakraborty, Jamuna; Das, Sukta

    2000-01-01

    The protective role of two commonly consumed natural dietary items- bitter gourd and tomato against endogenous as well as 7,12- dimethylbenz(a)anthracene (DMBA) induced lipid peroxidation in the livers of mice was investigated. The rationale for such an approach is that lipid peroxidation has been suggested to play a key role in human cancer development. There was a sharp rise in lipid peroxidation (measured as thiobarbituric acid reactive substances formation) during skin carcinogenesis induced by DMBA in mice. Aqueous extracts of bitter gourd and tomato juice were found to be very potent inhibitors of lipid peroxidation both in normal and DMBA treated mice. Our observations support the hypothesis that natural combinations of phytochemicals present in the fruit juices exert cancer-protective effects via a decrease in lipid peroxidation.

  2. Deletion of epidermal Rac1 inhibits HPV-8 induced skin papilloma formation and facilitates HPV-8- and UV-light induced skin carcinogenesis

    PubMed Central

    Deshmukh, Jayesh; Pofahl, Ruth; Pfister, Herbert; Haase, Ingo

    2016-01-01

    Overexpression and increased activity of the small Rho GTPase Rac1 has been linked to squamous cell carcinoma of the epidermis and mucosa in humans. Targeted deletion of Rac1 or inhibition of Rac1 activity in epidermal keratinocytes reduced papilloma formation in a chemical skin carcinogenesis mouse model. However, a potential role of Rac1 in HPV- and UV-light induced skin carcinogenesis has not been investigated so far, solar UV radiation being an important carcinogen to the skin. To investigate this, we deleted Rac1 or modulated its activity in mice with transgenic expression of Human papilloma virus type-8 (HPV-8) in epidermal keratinocytes. Our data show that inhibition or deletion of Rac1 results in reduced papilloma formation upon UV-irradiation with a single dose, whereas constitutive activation of Rac1 strongly increases papilloma frequency in these mice. Surprisingly, we observed that, upon chronic UV-irradiation, the majority of mice with transgenic expression of HPV-8 and epidermis specific Rac1 deletion developed squamous cell carcinomas. Taken together, our data show that Rac1 exerts a dual role in skin carcinogenesis: its activation is, on one hand, required for HPV-8- and UV-light induced papilloma formation but, on the other, suppresses the development of squamous cell carcinomas. PMID:27506937

  3. Deletion of epidermal Rac1 inhibits HPV-8 induced skin papilloma formation and facilitates HPV-8- and UV-light induced skin carcinogenesis.

    PubMed

    Deshmukh, Jayesh; Pofahl, Ruth; Pfister, Herbert; Haase, Ingo

    2016-09-06

    Overexpression and increased activity of the small Rho GTPase Rac1 has been linked to squamous cell carcinoma of the epidermis and mucosa in humans. Targeted deletion of Rac1 or inhibition of Rac1 activity in epidermal keratinocytes reduced papilloma formation in a chemical skin carcinogenesis mouse model. However, a potential role of Rac1 in HPV- and UV-light induced skin carcinogenesis has not been investigated so far, solar UV radiation being an important carcinogen to the skin.To investigate this, we deleted Rac1 or modulated its activity in mice with transgenic expression of Human papilloma virus type-8 (HPV-8) in epidermal keratinocytes. Our data show that inhibition or deletion of Rac1 results in reduced papilloma formation upon UV-irradiation with a single dose, whereas constitutive activation of Rac1 strongly increases papilloma frequency in these mice. Surprisingly, we observed that, upon chronic UV-irradiation, the majority of mice with transgenic expression of HPV-8 and epidermis specific Rac1 deletion developed squamous cell carcinomas. Taken together, our data show that Rac1 exerts a dual role in skin carcinogenesis: its activation is, on one hand, required for HPV-8- and UV-light induced papilloma formation but, on the other, suppresses the development of squamous cell carcinomas.

  4. Diosmin Protects against Ethanol-Induced Gastric Injury in Rats: Novel Anti-Ulcer Actions

    PubMed Central

    Arab, Hany H.; Salama, Samir A.; Omar, Hany A.; Arafa, El-Shaimaa A.; Maghrabi, Ibrahim A.

    2015-01-01

    Alcohol consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Diosmin (DIO) is a natural citrus flavone with remarkable antioxidant and anti-inflammatory features that underlay its protection against cardiac, hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus, the current study aimed to investigate the potential protective effects of DIO against ethanol-induced gastric injury in rats. Pretreatment with DIO (100 mg/kg p.o.) attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of ulcer index (UI) scores, area of gastric lesions, histopathologic aberrations and leukocyte invasion. These actions were analogous to those exerted by the reference antiulcer sucralfate. DIO suppressed gastric inflammation by curbing of myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) levels along with nuclear factor kappa B (NF-κB) p65 expression. It also augmented the anti-inflammatory interleukin-10 (IL-10) levels. Meanwhile, DIO halted gastric oxidative stress via inhibition of lipid peroxides with concomitant enhancement of glutathione (GSH), glutathione peroxidase (GPx) and the total antioxidant capacity (TAC). With respect to gastric mucosal apoptosis, DIO suppressed caspase-3 activity and cytochrome C (Cyt C) with enhancement of the anti-apoptotic B cell lymphoma-2 (Bcl-2) in favor of cell survival. These favorable actions were associated with upregulation of the gastric cytoprotective prostaglandin E2 (PGE2) and nitric oxide (NO). Together, these findings accentuate the gastroprotective actions of DIO in ethanol gastric injury which were mediated via concerted multi-pronged actions, including suppression of gastric inflammation, oxidative stress and apoptosis besides boosting of the antioxidant and the cytoprotective defenses. PMID:25821971

  5. Protective effect of hydrogen sulfide against cold restraint stress-induced gastric mucosal injury in rats.

    PubMed

    Aboubakr, Esam M; Taye, Ashraf; El-Moselhy, Mohamed A; Hassan, Magdy K

    2013-12-01

    Hydrogen sulfide (H2S) is an endogenous gaseous mediator plays a potential role in modulating gastric inflammatory responses. However, its putative protective role remains to be defined. The present study aimed to evaluate role of the exogenously released and endogenously synthesized H2S in cold restraint stress (CRS)-induced oxidative gastric damage in rats. Rats were restrained, and maintained at 4 °C for 3 h. The H2S donor, sodium hydrosulfide (NaHS) (60 μmol/kg) was injected intraperitoneally (i.p.) before CRS. Our results revealed that NaHS pretreatment significantly attenuated ulcer index, free and total acid output, and pepsin activity in gastric juice along with decreased gastric mucosal carbonyl content and reactive oxygen species production. This was accompanied by increased gastric juice pH and mucin concentration in addition to restoring the deficits in the gastric reduced glutathione, catalase as well as superoxide dismutase enzyme activities. NaHS pretreatment markedly reduced the serum level of tumor necrosis factor (TNF-α) and myeloperoxidase activity compared to CRS-non-treated. Moreover, NaHS preadministration significantly abrogated the inflammatory and the deleterious responses of gastric mucosa in CRS. The protective effects of H2S were confirmed by gastric histopathological examination. However, pretreatment with the H2S-synthesizing enzyme, cystathionine-gamma-lyase inhibitor, beta-cyano-L-alanine (50 mg/kg, i.p.) reversed the gastroprotection afforded by the endogenous H2S. Collectively, our results suggest that H2S can protect rat gastric mucosa against CRS-induced gastric ulceration possibly through mechanisms that involve anti-oxidant and anti-inflammatory actions alongside enhancement of gastric mucosal barrier and reduction in acid secretory parameters.

  6. Genetic ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis: the involvement of keratin-17

    PubMed Central

    Lee, Mee-Hyun; Lim, Do Young; Kim, Myoung Ok; Lee, Sung-Young; Shin, Seung Ho; Kim, Jae Young; Kim, Sung-Hyun; Kim, Dong Joon; Jung, Sung Keun; Yao, Ke; Kundu, Joydeb Kumar; Lee, Hye Suk; Lee, Cheol-Jung; Dickinson, Sally E.; Alberts, David; Bowden, G.Timothy; Stratton, Steven; Curiel, Clara; Einspahr, Janine; Bode, Ann M.; Surh, Young-Joon; Dong, Zigang

    2015-01-01

    Solar ultraviolet irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is reportedly expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancer and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic deficiency of caspase-7 are highly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and the average number of tumors were significantly increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation markers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. Two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. The expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study demonstrates that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17. PMID:26271098

  7. Genetic ablation of caspase-7 promotes solar-simulated light-induced mouse skin carcinogenesis: the involvement of keratin-17.

    PubMed

    Lee, Mee-Hyun; Lim, Do Young; Kim, Myoung Ok; Lee, Sung-Young; Shin, Seung Ho; Kim, Jae Young; Kim, Sung-Hyun; Kim, Dong Joon; Jung, Sung Keun; Yao, Ke; Kundu, Joydeb Kumar; Lee, Hye Suk; Lee, Cheol-Jung; Dickinson, Sally E; Alberts, David; Bowden, G Timothy; Stratton, Steven; Curiel, Clara; Einspahr, Janine; Bode, Ann M; Surh, Young-Joon; Cho, Yong-Yeon; Dong, Zigang

    2015-11-01

    Solar ultraviolet irradiation is an environmental carcinogen that causes skin cancer. Caspase-7 is reportedly expressed at reduced levels in many cancers. The present study was designed to examine the role of caspase-7 in solar-simulated light (SSL)-induced skin cancer and to elucidate its underlying molecular mechanisms. Our study revealed that mice with genetic deficiency of caspase-7 are highly susceptible to SSL-induced skin carcinogenesis. Epidermal hyperplasia, tumor volume and the average number of tumors were significantly increased in caspase-7 knockout (KO) mice compared with SKH1 wild-type mice irradiated with SSL. The expression of cell proliferation markers, such as survivin and Ki-67, was elevated in SSL-irradiated skin of caspase-7 KO mice compared with those observed in SSL-exposed wild-type SKH1 mouse skin. Moreover, SSL-induced apoptosis was abolished in skin from caspase-7 KO mice. Two-dimensional gel electrophoresis, followed by matrix-assisted laser desorption/ionization-time-of-flight analysis of skin tissue lysates from SSL-irradiated SKH1 wild-type and caspase-7 KO mice revealed an aberrant induction of keratin-17 in caspase-7 KO mice. Immunohistochemical analysis of skin tumors also showed an increase of keratin-17 expression in caspase-7 KO mice compared with SKH1 wild-type mice. The expression of keratin-17 was also elevated in SSL-irradiated caspase-7 KO keratinocytes as well as in human basal cell carcinomas. The in vitro caspase activity assay showed keratin-17 as a substrate of caspase-7, but not caspase-3. Overall, our study demonstrates that genetic loss of caspase-7 promotes SSL-induced skin carcinogenesis by blocking caspase-7-mediated cleavage of keratin-17. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Chemomodulatory Potential of Bartogenic Acid Against DMBA/Croton Oil Induced Two-Step Skin Carcinogenesis in Mice

    PubMed Central

    Patil, Chandragouda R.; Sonara, Bhavin M.; Mahajan, Umesh B.; Patil, Kalpesh R.; Patil, Dipak D.; Jadhav, Ramchandra B.; Goyal, Sameer N.; Ojha, Shreesh

    2016-01-01

    Barringtonia racemosa fruits are believed to be useful in cancer treatment in Ayurveda, the Indian system of medicine. In present study, bartogenic acid (BA), a triterpenoid constituent of Barringtonia fruits was evaluated for its cytotoxicity property using the human skin carcinoma cell line (SCC-13) and human peripheral blood mononuclear cells (PBMC). The chemopreventive efficacy of BA was evaluated against the DMBA/Croton oil-induced skin carcinogenesis in mice.BA was orally administered at the doses of 1, 2 or 4 mg/kg/day or applied topically every day for 12 weeks following DMBA application. The in vitro data from cell lines revealed that BA induces cytotoxicity against the SCC-13 cells (IC50=7.5 µM). It was found 4.05 times more selective to exert cytotoxicity against SCC-13 as compared to the PBMC (IC50=30.4 µM). The in vivo datacollected from mice model of DMBA/Croton oil-induced skin carcinogenesis revealed that BA administered orally or applied topically, both reduced the precancerous skin lesions andthe incidence of tumor bearing. The oral doses of BA (2 and 4 mg/kg) and topical treatment significantly reduced the incidence and number of skin papillomas. At these doses, BA also increased the activities of catalase and superoxide dismutase and induced an increase in glutathionecontent and inhibited lipid peroxidation in the skin. These findings reveal the chemopreventive efficacy of BA and also demonstrate that it contributes to the cytotoxic and antioxidative effects of Barringtonia racemosa fruits. The study also validates the traditional claims of Barringtonia fruits and provides a scientific basis of its chemopreventive property. PMID:27877231

  9. Chemopreventive activity of apple extract following medium-term oral carcinogenesis assay induced by 4-nitroquinoline-1-oxide.

    PubMed

    Ribeiro, Flávia Andressa Pidone; de Moura, Carolina Foot Gomes; Gollucke, Andrea Pitelli Boiago; Ferreira, Mônica Siqueira; Catharino, Rodrigo Ramos; Aguiar, Odair; Spadari, Regina Celia; Barbisan, Luis Fernando; Ribeiro, Daniel Araki

    2014-08-01

    The aim of this study was to evaluate the chemopreventive activity of an apple extract following medium-term oral carcinogenesis assay induced by 4-nitroquinoline-1-oxide (4NQO). A total of 30 male Wistar rats were distributed into five groups as follows (n=6 per group): Group 1, negative control group (non-treated group); Group 2, received 4NQO during 8 weeks in drinking water and treated with apple extract at 1% by gavage between the first and fourth weeks daily (initiation phase); Group 3, received 4NQO for 8 weeks in drinking water and treated with apple extract by gavage at 1% between the fifth and eighth weeks daily (promotion phase); Group 4, received apple extract at 1% by gavage for 8 consecutive weeks only; and Group 5, received 4NQO for 8 weeks in drinking water daily. Histopathological analysis revealed decreased hyperplasic lesions in Group 2 when compared with Group 5. Likewise, decreased dysplastic lesions in Group 3 were observed when compared with Group 5. In Groups 2 and 3, decreased COX-2 and TNF-alpha gene expressions were observed when compared with Group 5. Cytochrome c and caspase 3 levels increased in Groups 2 and 3 when compared with Group 5. In conclusion, our results demonstrate that apple extract suppresses rat tongue carcinogenesis as a result of anti-inflammatory activity and apoptosis through the intrinsic mitochondrial pathway. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Institutional Animal Care and Use Committee Considerations Regarding the Use of Virus-Induced Carcinogenesis and Oncolytic Viral Models.

    PubMed

    Lewis, Stephanie D; Hickman-Davis, Judy M; Bergdall, Valerie K

    2016-01-01

    The use of virus-induced carcinogenesis and oncologic experimental animal models is essential in understanding the mechanisms of cancer development to advance prevention, diagnosis, and treatment methods. The Institutional Animal Care and Use Committee (IACUC) is responsible for both the complex philosophical and practical considerations associated with animal models of cancer. Animal models of cancer carry their own unique issues that require special consideration from the IACUC. Many of the considerations to be discussed apply to cancer models in general; specific issues related to viral carcinogenesis or oncolytic viruses will be specifically discussed as they arise. Responsible animal use integrates good science, humane care, and regulatory compliance. To meet those standards, the IACUC, in conjunction with the research investigator and attending veterinarian, must address a wide range of issues, including animal model selection, cancer model selection, humane end point considerations, experimental considerations, postapproval monitoring, reporting requirements, and animal management and personnel safety considerations. © The Author 2016. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  11. Korean Solar Salt Ameliorates Colon Carcinogenesis in an AOM/DSS-Induced C57BL/6 Mouse Model.

    PubMed

    Ju, Jaehyun; Kim, Yeung-Ju; Park, Eui Seong; Park, Kun-Young

    2017-06-01

    The effects of Korean solar salt on an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon cancer C57BL/6 mouse model were studied. Korean solar salt samples (SS-S, solar salt from S salt field; SS-Yb, solar salt from Yb salt field), nine-time-baked bamboo salt (BS-9x, made from SS-Yb), purified salt (PS), and SS-G (solar salt from Guérande, France) were orally administered at a concentration of 1% during AOM/DSS colon cancer induction, and compared for their protective effects during colon carcinogenesis in C57BL/6 mice. SS-S and SS-Yb suppressed colon length shortening and tumor counts in mouse colons. Histological evaluation by hematoxylin and eosin staining also revealed suppression of tumorigenesis by SS-S. Conversely, PS and SS-G did not show a similar suppressive efficacy as Korean solar salt. SS-S and SS-Yb promoted colon mRNA expression of an apoptosis-related factor and cell-cycle-related gene and suppressed pro-inflammatory factor. SS-Yb baked into BS-9x further promoted these anti-carcinogenic efficacies. Taken together, the results indicate that Korean solar salt, especially SS-S and SS-Yb, exhibited anti-cancer activity by modulating apoptosis- and inflammation-related gene expression during colon carcinogenesis in mice, and bamboo salt baked from SS-Yb showed enhanced anti-cancer functionality.

  12. Charles River Sprague Dawley Rats Lack Early Age-Dependent Susceptibility to DMBA-Induced Mammary Carcinogenesis

    PubMed Central

    Gear, R.B.; Yan, M.; Schneider, J.; Succop, P.; Heffelfinger, S.C.; Clegg, D.J.

    2007-01-01

    Developmental stages of mammary glands influence their susceptibility to initiating events related to carcinogenesis. The “window of susceptibility” to mammary carcinogenesis is classically defined as the time in early puberty when the mammary gland morphology is most sensitive to initiation events. Administration of the polyaromatic hydrocarbon, 7,12-dimethylbenz(a)anthracene (DMBA), in a single oral dose yields maximal mammary tumor formation when administered in this “window”. We examined the DMBA treated mammary glands, precursor lesions, and morphology of the uninvolved mammary epithelium for the first 100 days of life for Charles River Sprague Dawley CDR IGS. Our goal was to determine the DMBA dose at which 50% of the rats (IC50) developed carcinoma in situ (CIS) within three months of dosing. Here we demonstrate, rather than the classical U-shaped dose curve in which there is maximum sensitivity for DMBA at 50 days, there is an increasing degree of sensitivity with age in the CDR IGS rat. Additionally, we report that vehicle-treated animals developed mammary CIS without any known initiator, and 100 day virgin animals demonstrated lactational changes, independent of DMBA exposure or dose. Lastly, we demonstrate this strain of virgin female rats has elevated pituitary prolactin immunoreactivity independent of the level of mammary differentiation. We conclude this strain of Charles River Sprague Dawley rats has prolactin-induced pituitary stimulation, and therefore, the window of susceptibility for mammary tumorigenesis is absent. PMID:17940635

  13. Effect of IL-1β and IL-1RN polymorphisms in carcinogenesis of the gastric mucosa in patients infected with Helicobacter pylori in Algeria.

    PubMed

    Drici, Amine El-Mokhtar; Moulessehoul, Soraya; Tifrit, Abdelkarim; Diaf, Mustapha; Turki, Douidi Kara; Bachir, Meryem; Tou, Abdenacer

    2016-01-01

    Infection with Helicobacter pylori is considered a potential risk of developing gastric cancer in association with contributing host genetic factor. IL-1β and IL-1RN polymorphisms appear to maintain and promote Helicobacter pylori infection and to stimulate neoplastic growth of the gastric mucosa. In order to elucidate the effect of these polymorphisms in combination with gastric cancer in a population from northwestern Algeria, a case-control study was carried out on 79 patients infected with H. pylori with chronic atrophic gastritis and/or gastric carcinoma, and 32 subjects were recruited as case-control. IL-1β-31 bi-allelic and IL-1β-511 bi-allelic polymorphisms and IL-1RN penta-allelic were genotyped. IL-1β-31C was associated with an increased risk of developing gastric carcinoma (OR=4.614 [1.43-14.81], p=0.01). However, IL-1RN2 heterozygous allele type was significantly associated with chronic atrophic gastritis (OR=4.2 [1.23-3.61], p=0.022). IL-1β-511T was associated with an increased risk of development of chronic atrophic gastritis (OR=4.286 [1.54-11.89], p=0.005). IL-1β and IL-1RN polymorphisms associated with H. pylori infection contribute to the development of chronic atrophic gastritis and gastric carcinomas in an Algerian population. The alleles IL-1β-31C and IL-1RN were associated with an increased risk of developing gastric carcinoma, and IL-1β-511T with an increased risk of developing chronic atrophic gastritis with no significant association of developing gastric carcinoma.

  14. Effect of IL-1β and IL-1RN polymorphisms in carcinogenesis of the gastric mucosa in patients infected with Helicobacter pylori in Algeria

    PubMed Central

    Drici, Amine El-Mokhtar; Moulessehoul, Soraya; Tifrit, Abdelkarim; Diaf, Mustapha; Turki, Douidi Kara; Bachir, Meryem; Tou, Abdenacer

    2016-01-01

    Background Infection with Helicobacter pylori is considered a potential risk of developing gastric cancer in association with contributing host genetic factor. IL-1β and IL-1RN polymorphisms appear to maintain and promote Helicobacter pylori infection and to stimulate neoplastic growth of the gastric mucosa. Objective and methods In order to elucidate the effect of these polymorphisms in combination with gastric cancer in a population from northwestern Algeria, a case-control study was carried out on 79 patients infected with H. pylori with chronic atrophic gastritis and/or gastric carcinoma, and 32 subjects were recruited as case-control. IL-1β-31 bi-allelic and IL-1β-511 bi-allelic polymorphisms and IL-1RN penta-allelic were genotyped. Results IL-1β-31C was associated with an increased risk of developing gastric carcinoma (OR=4.614 [1.43−14.81], p=0.01). However, IL-1RN2 heterozygous allele type was significantly associated with chronic atrophic gastritis (OR=4.2 [1.23−3.61], p=0.022). IL-1β-511T was associated with an increased risk of development of chronic atrophic gastritis (OR=4.286 [1.54−11.89], p=0.005). Conclusion IL-1β and IL-1RN polymorphisms associated with H. pylori infection contribute to the development of chronic atrophic gastritis and gastric carcinomas in an Algerian population. The alleles IL-1β-31C and IL-1RN were associated with an increased risk of developing gastric carcinoma, and IL-1β-511T with an increased risk of developing chronic atrophic gastritis with no significant association of developing gastric carcinoma. PMID:27340011

  15. Targeting hepatitis B virus and human papillomavirus induced carcinogenesis: novel patented therapeutics.

    PubMed

    Kanwar, Rupinder K; Singh, Neha; Gurudevan, Sneha; Kanwar, Jagat R

    2011-05-01

    Viral infections leading to carcinogenesis tops the risk factors list for the development of human cancer. The decades of research has provided ample scientific evidence that directly links 10-15% of the worldwide incidence of human cancers to the infections with seven human viruses. Moreover, the insights gained into the molecular pathogenetic and immune mechanisms of hepatitis B virus (HBV) and human papillomavirus (HPV) viral transmission to tumour progression, and the identification of their viral surface antigens as well as oncoproteins have provided the scientific community with opportunities to target these virus infections through the development of prophylactic vaccines and antiviral therapeutics. The preventive vaccination programmes targeting HBV and high risk HPV infections, linked to hepatocellular carcinoma (HCC) and cervical cancer respectively have been recently reported to alter age-old cancer patterns on an international scale. In this review, with an emphasis on HBV and HPV mediated carcinogenesis because of the similarities and differences in their global incidence patterns, viral transmission, mortality, molecular pathogenesis and prevention, we focus on the development of recently identified HBV and HPV targeting innovative strategies resulting in several patents and patent applications.

  16. Gastroprotective effect of aucubin against ethanol-induced gastric mucosal injury in mice.

    PubMed

    Yang, Yang; Yin, Bing; Lv, Le; Wang, Ziye; He, Jiao; Chen, Ziyang; Wen, Xin; Zhang, Yongmin; Sun, Wenji; Li, Yang; Zhao, Ye

    2017-09-14

    Aucubin, an iridoid glycoside, was isolated from seeds of Eucommia ulmoides Oliver. This study was aimed to evaluate the protective effect of aucubin against ethanol-induced gastric mucosal injury in mice. Mice were orally administrated with aucubin (20, 40 and 80mg/kg) for 3 consecutive days. On the 3rd day, the mice of gastric mucosal injury were induced with 70% ethanol after the last administration of aucubin. Gastric tissue of mice were submitted for evaluating the severity of gastric mucosal injury. The protective effect of aucubin was evaluated by the gastric ulcer index and histological examinations and determining the levels of inflammatory cytokines, oxidative stress and some gastric mucosal protection factors. Prophylactic oral administration of aucubin decreased gastric ulcer indexes and histological scores. A significant decrease of myeloperoxidase (MPO) activity and the levels of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were observed in aucubin administrated groups. In addition, mice administrated with aucubin increased glutathione (GSH) and heat shock protein-70 (HSP-70) levels and superoxide dismutase (SOD) activity, as well as normalized the levels of epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and cyclooxygenase-1 (COX-1) in gastric tissue of mice. The findings of this study demonstrated that aucubin shows protective effect against ethanol-induced acute gastric mucosal injury through its anti-inflammatory and anti-oxidant effects. Furthermore, aucubin enhanced gastric mucosal protection by up-regulation of HSP-70 level and normalization of EGF, VEGF and COX-1 levels. Copyright © 2017. Published by Elsevier Inc.

  17. Protective effect of Calotropis procera latex extracts on experimentally induced gastric ulcers in rat.

    PubMed

    Bharti, S; Wahane, V D; Kumar, V L

    2010-02-03

    Calotropis procera is a wild growing plant with multifarious medicinal properties. The present study was carried out to evaluate the effect of dried latex (DL) of Calotropis procera and its methanol extract (MeDL) against gastric ulcers induced in rats. Aqueous suspension of DL (20 and 100mg/kg) and MeDL (10 and 50mg/kg) were given orally to 36h fasted rats and ulcers were induced by ethanol, pyloric ligation and aspirin. Parameters like ulcer score and levels of oxidative stress markers were measured in all the models. The effect on gastric hemorrhage and tissue histology was studied in ethanol model and on acidity, pH and volume of gastric secretion was evaluated in pyloric ligation model. The protective effect of DL and MeDL was compared with that of standard anti-ulcer drug famotidine (20 mg/kg). DL and MeDL produced 85-95% inhibition of gastric mucosal damage in ethanol model and 70-80% inhibition in aspirin model. The protective effect of these extracts was associated with marked reduction in gastric hemorrhage, maintenance of tissue integrity and normalization of levels of oxidative stress markers like glutathione, thiobarbituric acid reactive substances and superoxide dismutase. Like famotidine, DL and MeDL decreased the gastric acidity from 376.17+/-21.47 mequiv./l to 163.88+/-6.86 and 201.48+/-8.86 mequiv./l respectively in pyloric ligation model. These extracts increased the gastric pH without affording any protection to gastric mucosa in this model. The latex of Calotropis procera has the therapeutic potential to relieve gastric hyperacidity and to prevent gastric ulceration induced by necrotizing agents. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

  18. Depletion of HPV16 early genes induces autophagy and senescence in a cervical carcinogenesis model, regardless of viral physical state.

    PubMed

    Hanning, Jennifer E; Saini, Harpreet K; Murray, Matthew J; Caffarel, Maria M; van Dongen, Stijn; Ward, Dawn; Barker, Emily M; Scarpini, Cinzia G; Groves, Ian J; Stanley, Margaret A; Enright, Anton J; Pett, Mark R; Coleman, Nicholas

    2013-11-01

    In cervical carcinomas, high-risk human papillomavirus (HR-HPV) may be integrated into host chromosomes or remain extra-chromosomal (episomal). We used the W12 cervical keratinocyte model to investigate the effects of HPV16 early gene depletion on in vitro cervical carcinogenesis pathways, particularly effects shared by cells with episomal versus integrated HPV16 DNA. Importantly, we were able to study the specific cellular consequences of viral gene depletion by using short interfering RNAs known not to cause phenotypic or transcriptional off-target effects in keratinocytes. We found that while cervical neoplastic progression in vitro was characterized by dynamic changes in HPV16 transcript levels, viral early gene expression was required for cell survival at all stages of carcinogenesis, regardless of viral physical state, levels of early gene expression or histology in organotypic tissue culture. Moreover, HPV16 early gene depletion induced changes in host gene expression that were common to both episome-containing and integrant-containing cells. In particular, we observed up-regulation of autophagy genes, associated with enrichment of senescence and innate immune-response pathways, including the senescence-associated secretory phenotype (SASP). In keeping with these observations, HPV16 early gene depletion induced autophagy in both episome-containing and integrant-containing W12 cells, as evidenced by the appearance of autophagosomes, punctate expression of the autophagy marker LC3, conversion of LC3B-I to LC3B-II, and reduced levels of the autophagy substrate p62. Consistent with the reported association between autophagy and senescence pathways, HPV16 early gene depletion induced expression of the senescence marker beta-galactosidase and increased secretion of the SASP-related protein IGFBP3. Together, these data indicate that depleting HR-HPV early genes would be of potential therapeutic benefit in all cervical carcinogenesis pathways, regardless of viral

  19. Clonal xenobiotic resistance during pollution-induced toxic injury and hepatocellular carcinogenesis in liver of female flounder (Platichthys flesus (L.)).

    PubMed

    Koehler, Angela; Alpermann, Tilmann; Lauritzen, Bjarne; Van Noorden, Cornelis J F

    2004-01-01

    Juvenile and adult female flounder (Platichthys flesus (L.)) were caught either in the estuary of the most polluted European river, the Elbe, or as controls in a reference site to study pollution-induced xenobiotic resistance in their livers in relation to pathological alterations. In juvenile fish, livers displayed reversible and irreversible degenerative toxipathic lesion types but never showed (pre)neoplastic changes. Tumour frequencies up to 70% were found macroscopically in livers of adult female flounder which had progressed to adenomas and carcinomas in the most polluted site. Because male adult flounder show only up to 50% of livers containing early preneoplastic foci but never malignancies, we focussed our study on female individuals. (Pre)neoplastic changes ranged from early eosinophilic foci to basophilic foci, adenomas and hepatocellular carcinomas. Adenomas were generally eosinophilic whereas carcinomas were mainly basophilic. These phenotypical sequential changes strongly resemble those found in chemically-induced liver carcinogenesis in mammals. Characteristic mutations known from mammalian cancers have not been found so far in these flounder livers. Therefore, we investigated whether epigenetic events had induced a metabolic "resistant phenotype" of (pre)malignant cancer cells during hepatocellular carcinogenesis. With a quantitative immunohistochemical approach, we studied expression of P-glycoprotein (P-gp)-mediated multixenobiotic resistance (MXR), cytochrome P4501A1, glutathione-S-transferase-A which are key proteins in xenobiotic metabolism and elimination. Glucose-6-phosphate dehydrogenase (G6PDH) activity, the major source of the reducing power NADPH which is needed for biotransformation, oxyradical scavenging and biosynthesis, was detected as well. We observed upregulation of G6PDH activity already in early preneoplastic eosinophilic foci and subsequent further upregulation in basophilic foci and carcinomas. P-gp started to become

  20. Pathobiology of Helicobacter pylori-induced Gastric Cancer

    PubMed Central

    Amieva, Manuel; Peek, Richard M.

    2015-01-01

    Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data indicate that subtle mismatches between host and microbe genetic traits greatly affect risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness demonstrates the sophisticated relationship among H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori’s activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism. PMID:26385073

  1. Pathobiology of Helicobacter pylori-Induced Gastric Cancer.

    PubMed

    Amieva, Manuel; Peek, Richard M

    2016-01-01

    Colonization of the human stomach by Helicobacter pylori and its role in causing gastric cancer is one of the richest examples of a complex relationship among human cells, microbes, and their environment. It is also a puzzle of enormous medical importance given the incidence and lethality of gastric cancer worldwide. We review recent findings that have changed how we view these relationships and affected the direction of gastric cancer research. For example, recent data have indicated that subtle mismatches between host and microbe genetic traits greatly affect the risk of gastric cancer. The ability of H pylori and its oncoprotein CagA to reprogram epithelial cells and activate properties of stemness show the sophisticated relationship between H pylori and progenitor cells in the gastric mucosa. The observation that cell-associated H pylori can colonize the gastric glands and directly affect precursor and stem cells supports these observations. The ability to mimic these interactions in human gastric organoid cultures as well as animal models will allow investigators to more fully unravel the extent of H pylori control on the renewing gastric epithelium. Finally, our realization that external environmental factors, such as dietary components and essential micronutrients, as well as the gastrointestinal microbiota, can change the balance between H pylori's activity as a commensal or a pathogen has provided direction to studies aimed at defining the full carcinogenic potential of this organism. Copyright © 2016. Published by Elsevier Inc.

  2. Topographic localization of gastric lesions and key role of plasma bicarbonate concentration in dogs with experimentally induced gastric dilatation.

    PubMed

    Pfeiffer, C J; Keith, J C; April, M

    1987-02-01

    The canine gastric response to acute dilatation, its correlation with selected systemic cardiovascular changes, and preliminary study of its modulation by membrane-stabilizing agents were studied in 21 Beagle dogs. Gastric mucosal damage and adverse cardiovascular sequelae were induced by inflation of an intragastric balloon to 60 mm of Hg in each anesthetized dog for 2.5 hours. At this time, dogs were given 1 of 4 treatments: control; lidocaine HCl, 2.2 mg bolus + 66 micrograms/min, IV; prednisolone succinate, 6.6 mg, IV; and zinc sulfate, 2.2 mg bolus + 66 micrograms/min, IV. After treatments were given, there was a 4-hour deflation period. Throughout the 6.5 hours, continuous measurements were made of stroke volume, arterial blood pressure, PaO2, PaCO2, and plasma HCO3- concentration. Gastric lesions, assessed by planimetric analysis of ulcer indices, were limited to the fundus and corpus and were significantly decreased by lidocaine administration. As seen by histopathologic examination, a sharply delineated transverse area bordering the corporeal-antral junction near the lesser curvature demonstrated minimal resistance to ulceration and showed mucus depletion. Plasma HCO3- concentration, base excess, and CO2 values were negatively correlated with development of gastric damage, indicating that plasma HCO3- concentration has a key role in mucosal resistance to ulcerogenesis.

  3. L-Theanine healed NSAID-induced gastric ulcer by modulating pro/antioxidant balance in gastric ulcer margin.

    PubMed

    Chatterjee, Sirshendu; Chatterjee, Ananya; Roy, Surmi; Bera, Biswajit; Bandyopadhyay, Sandip K

    2014-10-01

    L-Theanine is a unique non-protein-forming amino acid present in tea [Camellia sinensis (L.) O. Kuntze]. In the present work, we evaluated the healing effect of L-theanine on NSAID (indomethacin)-induced gastric ulcer. Histology of the stomach tissues revealed maximum ulceration on the third day after indomethacin administration (18 mg/kg, single dose p.o.) which was accompanied by increased lipid peroxidation; protein carbonylation; Th1 cytokine synthesis, and depletion of thiol, mucin, prostaglandin (PG) E, Th2 cytokine synthesis; and total antioxidant status in mice. L-Theanine healed gastric ulcer at a dose of 10 mg/kg b.w. but aggravated the ulcerated condition at a higher dose of 40 mg/kg b.w. At 10 mg/kg b.w., L-theanine significantly alleviated the adverse oxidative effect of indomethacin through enhanced synthesis of PGE2 by modulation of cyclo-oxygenase-1 and 2 [COX-1 and COX-2] expression, Th1/Th2 cytokine balance, and restoration of cellular antioxidant status at the gastric ulcer margin. The present study revealed for the first time the dose-dependent biphasic effect of a natural neuroprotective agent, L-theanine, on gastric ulcer disease.

  4. Evaluation of the chemopreventive response of naringenin-loaded nanoparticles in experimental oral carcinogenesis using laser-induced autofluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    Sulfikkarali, N. K.; Krishnakumar, N.

    2013-04-01

    The aim of the present study is to investigate the chemopreventive effects of prepared naringenin-loaded nanoparticles (NARNPs) relative to the efficacy of free naringenin (NAR) in modifying the carcinogenic process and to study the changes in the endogenous fluorophores during DMBA-induced hamster buccal pouch (HBP) carcinogenesis by laser-induced autofluorescence (LIAF) spectroscopy. LIAF emission spectra from the hamster buccal mucosa of the control and experimental groups of animals were recorded in the 350-700 nm spectral range on a miniature fiber optic spectrometer from different anatomical sites of each group, with excitation at 404 nm from a diode laser. Oral squamous cell carcinoma (OSCC) was developed in the buccal pouch of golden Syrian hamsters by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. DMBA-painted animals revealed morphological changes, hyperplasia, dysplasia and well-differentiated squamous cell carcinoma. LIAF emission spectra showed significant difference between the control and tumor tissues. The tumor tissues are characterized by an increase in the emission of porphyrins and a decrease in the emission of nicotinamide adenine dinucleotide hydrogenase (NADH) and flavin adenine nucleotide (FAD) when compared to the control tissues. Furthermore, oral administration of NAR and its nanoparticulates restored the status of endogenous fluorophores in the buccal mucosa of DMBA-painted animals. On a comparative basis, the treatment of nanoparticulate naringenin was found to be more effective than free naringenin in completely preventing the formation of squamous cell carcinoma and in improving the status of endogenous porphyrins to a normal range in DMBA-induced hamster buccal pouch carcinogenesis. The result of the present study further suggests that LIAF spectroscopy may be a very valuable tool for rapid and sensitive detection of endogenous fluorophore changes in response to chemopreventive agents.

  5. Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis

    PubMed Central

    Wirtz, Stefan; Nagel, Georg; Eshkind, Leonid; Neurath, Markus F.; Samson, Leona D.; Kaina, Bernd

    2010-01-01

    Methylating agents are widely distributed environmental carcinogens. Moreover, they are being used in cancer chemotherapy. The primary target of methylating agents is DNA, and therefore, DNA repair is the first-line barrier in defense against their toxic and carcinogenic effects. Methylating agents induce in the DNA O6-methylguanine (O6MeG) and methylations of the ring nitrogens of purines. The lesions are repaired by O6-methylguanine-DNA methyltransferase (Mgmt) and by enzymes of the base excision repair (BER) pathway, respectively. Whereas O6MeG is well established as a pre-carcinogenic lesion, little is known about the carcinogenic potency of base N-alkylation products such as N3-methyladenine and N3-methylguanine. To determine their role in cancer formation and the role of BER in cancer protection, we checked the response of mice with a targeted gene disruption of Mgmt or N-alkylpurine-DNA glycosylase (Aag) or both Mgmt and Aag, to azoxymethane (AOM)-induced colon carcinogenesis, using non-invasive mini-colonoscopy. We demonstrate that both Mgmt- and Aag-null mice show a higher colon cancer frequency than the wild-type. With a single low dose of AOM (3 mg/kg) Aag-null mice showed an even stronger tumor response than Mgmt-null mice. The data provide evidence that both BER initiated by Aag and O6MeG reversal by Mgmt are required for protection against alkylation-induced colon carcinogenesis. Further, the data indicate that non-repaired N-methylpurines are not only pre-toxic but also pre-carcinogenic DNA lesions. PMID:20732909

  6. Both base excision repair and O6-methylguanine-DNA methyltransferase protect against methylation-induced colon carcinogenesis.

    PubMed

    Wirtz, Stefan; Nagel, Georg; Eshkind, Leonid; Neurath, Markus F; Samson, Leona D; Kaina, Bernd

    2010-12-01

    Methylating agents are widely distributed environmental carcinogens. Moreover, they are being used in cancer chemotherapy. The primary target of methylating agents is DNA, and therefore, DNA repair is the first-line barrier in defense against their toxic and carcinogenic effects. Methylating agents induce in the DNA O(6)-methylguanine (O(6)MeG) and methylations of the ring nitrogens of purines. The lesions are repaired by O(6)-methylguanine-DNA methyltransferase (Mgmt) and by enzymes of the base excision repair (BER) pathway, respectively. Whereas O(6)MeG is well established as a pre-carcinogenic lesion, little is known about the carcinogenic potency of base N-alkylation products such as N3-methyladenine and N3-methylguanine. To determine their role in cancer formation and the role of BER in cancer protection, we checked the response of mice with a targeted gene disruption of Mgmt or N-alkylpurine-DNA glycosylase (Aag) or both Mgmt and Aag, to azoxymethane (AOM)-induced colon carcinogenesis, using non-invasive mini-colonoscopy. We demonstrate that both Mgmt- and Aag-null mice show a higher colon cancer frequency than the wild-type. With a single low dose of AOM (3 mg/kg) Aag-null mice showed an even stronger tumor response than Mgmt-null mice. The data provide evidence that both BER initiated by Aag and O(6)MeG reversal by Mgmt are required for protection against alkylation-induced colon carcinogenesis. Further, the data indicate that non-repaired N-methylpurines are not only pre-toxic but also pre-carcinogenic DNA lesions.

  7. α-Terpineol Induces Gastric Retention of Liquids by Inhibiting Vagal Parasympathetic Pathways in Rats.

    PubMed

    da Silva, Moisés Tolentino Bento; Marques, Rosemarie Brandim; Batista-Lima, Francisco José; Soares, Marília Almeida; Dos Santos, Armênio Aguiar; Magalhães, Pedro Jorge Caldas; de Assis Oliveira, Francisco; de Castro Almeida, Fernanda Regina

    2016-10-01

    α-Terpineol is a monoterpene with smooth muscle relaxant properties. In this study, its effects on the gastric emptying rate of awake rats were evaluated with emphasis on the mode by which it induces gastrointestinal actions. Administered by gavage, α-terpineol (50 mg/kg) delayed gastric emptying of a liquid test meal at 10 min postprandial. Hexamethonium or guanethidine did not interfere with the retarding effect induced by α-terpineol, but atropine and L-N(G)-nitroarginine methyl ester abolished it. In vagotomized rats, α-terpineol did not delay gastric emptying. In isolated strips of gastric fundus, concentration-effect curves in response to carbamylcholine were higher in magnitude after treatment with the monoterpene. α-Terpineol (1 to 2000 µM) relaxed sustained contractions induced by carbamylcholine or a high K(+) concentration in a concentration-dependent manner. This relaxing effect was not affected by the presence of L-N(G)-nitroarginine methyl ester, 1 H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, tetraethylammonium, or atropine. Smooth muscle contractions induced by electrical field stimulation were inhibited by α-terpineol. In conclusion, α-terpineol induced gastric retention in awake rats through mechanisms that depended on intact vagal innervation to the stomach, which involved cholinergic/nitrergic signalling. Such a retarding effect induced by α-terpineol appears not to result from a direct action of the monoterpene on gastric smooth muscle cells.

  8. Alteration of stomach microbiota compositions in the progression of gastritis induces nitric oxide in gastric cell

    PubMed Central

    Dong, Tianyi; Feng, Qiang; Liu, Fengyan; Chang, Lap Kam; Zhou, Xiangyu; Han, Mingyong; Tian, Xingsong; Zhong, Ning; Liu, Shili

    2017-01-01

    Atrophic gastritis is considered to be an antecedent to intestinal metaplasia and gastric cancer. A previous study identified that Helicobacter pylori was absent at the severe atrophic gastritis stage, and alterations in the gastric microbial composition resembled those in gastric cancer. To explore the role of the bacteria absence of H. pylori in gastric carcinogenesis, in the current study, we compared the microbiota of clinically collected H. pylori-free gastric fluids from 30 patients with non-atrophic gastritis (N) and 22 patients with severe atrophic gastritis (S). We estimated the bacterial loads in the N and S groups by colony counting in culture agar as well as by measuring the concentration of the extracted DNA. The results showed a significant increase in bacterial load in patients with atrophic gastritis in comparison to non-atrophic gastritis. Then, we analyzed the microbial communities of the gastric fluids from all 52 patients using high-throughput sequencing of 16S rRNA amplicons. The Chao 1, Shannon and Simpson diversity indexes demonstrated that the bacterial richness and diversity were not significantly different between the N and S groups. Moreover, principal component analysis illustrated that the microbiomes from the S group were more scattered. Microbiota composition analysis showed that the entire dataset was clustered into 27 phyla, 61 classes, 106 orders, 177 families, 292 genera and 121 species. At the genus level, only the abundance of Prevotella was significantly different between the N and S groups. Further analysis showed that all the higher taxonomic categories were significantly different between the N and S groups. To assess the effects of the metabolic products of Prevotella spp. on gastric cell physiology, we treated the human gastric epithelial cell line AGS with acetic acid and monitored nitric oxide (NO) production. The results showed that acetic acid at low concentrations (0.5 and 5 µM) significantly inhibited AGS cells to

  9. Alteration of stomach microbiota compositions in the progression of gastritis induces nitric oxide in gastric cell.

    PubMed

    Dong, Tianyi; Feng, Qiang; Liu, Fengyan; Chang, Lap Kam; Zhou, Xiangyu; Han, Mingyong; Tian, Xingsong; Zhong, Ning; Liu, Shili

    2017-06-01

    Atrophic gastritis is considered to be an antecedent to intestinal metaplasia and gastric cancer. A previous study identified that Helicobacter pylori was absent at the severe atrophic gastritis stage, and alterations in the gastric microbial composition resembled those in gastric cancer. To explore the role of the bacteria absence of H. pylori in gastric carcinogenesis, in the current study, we compared the microbiota of clinically collected H. pylori-free gastric fluids from 30 patients with non-atrophic gastritis (N) and 22 patients with severe atrophic gastritis (S). We estimated the bacterial loads in the N and S groups by colony counting in culture agar as well as by measuring the concentration of the extracted DNA. The results showed a significant increase in bacterial load in patients with atrophic gastritis in comparison to non-atrophic gastritis. Then, we analyzed the microbial communities of the gastric fluids from all 52 patients using high-throughput sequencing of 16S rRNA amplicons. The Chao 1, Shannon and Simpson diversity indexes demonstrated that the bacterial richness and diversity were not significantly different between the N and S groups. Moreover, principal component analysis illustrated that the microbiomes from the S group were more scattered. Microbiota composition analysis showed that the entire dataset was clustered into 27 phyla, 61 classes, 106 orders, 177 families, 292 genera and 121 species. At the genus level, only the abundance of Prevotella was significantly different between the N and S groups. Further analysis showed that all the higher taxonomic categories were significantly different between the N and S groups. To assess the effects of the metabolic products of Prevotella spp. on gastric cell physiology, we treated the human gastric epithelial cell line AGS with acetic acid and monitored nitric oxide (NO) production. The results showed that acetic acid at low concentrations (0.5 and 5 µM) significantly inhibited AGS cells to

  10. Curcumin attenuates gastric cancer induced by N-methyl-N-nitrosourea and saturated sodium chloride in rats.

    PubMed

    Sintara, Kawiya; Thong-Ngam, Duangporn; Patumraj, Suthiluk; Klaikeaw, Naruemon

    2012-01-01

    To determine effects of curcumin on N-methyl-N-nitrosourea (MNU) and saturated sodium chloride (s-NaCl)-induced gastric cancer in rats. Male Wistar rats were divided into 5 groups: control (CO), control supplemented with 200 mg/kg curcumin (CC), MNU + s-NaCl, MNU + s-NaCl supplemented with 200 mg/kg curcumin daily for the first 3 weeks (MNU + s-NaCl + C3W), and MNU + s-NaCl supplemented with curcumin for 20 weeks (MNU + s-NaCl + C20W). To induce stomach cancer, rats except for CO and CC were orally treated with 100 mg/kg MNU on day 0 and 14, and s-NaCl twice-a-week for the first 3 weeks. The experiment was finished and rats were sacrificed at the end of 20 weeks. Cancers were found in forestomachs of all rats in MNU + s-NaCl. The expressions of phosphorylated inhibitor kappaB alpha (phospho-IκBα), 8-hydroxy-2'-deoxyguanosine (8-OHdG), and cyclin D1 significantly increased in MNU + s-NaCl compared with CO. Curcumin treatments for 3 and 20 weeks reduced the cancer incidence resulting in a decrease of phospho-IκBα expression in benign tumor-bearing rats compared with MNU + s-NaCl. Curcumin treatment for 20 weeks also decreased 8-OHdG expression in benign tumor-bearing rats compared with MNU + s-NaCl. Curcumin can attenuate cancer via a reduction of phospho-IκBα and 8-OHdG expressions, which may play a promising role in gastric carcinogenesis.

  11. Pharmacological evidence for the participation of NO-cGMP-KATP pathway in the gastric protective effect of curcumin against indomethacin-induced gastric injury in the rat.

    PubMed

    Díaz-Triste, Nadia Estela; González-García, Martha Patricia; Jiménez-Andrade, Juan Miguel; Castañeda-Hernández, Gilberto; Chávez-Piña, Aracely Evangelina

    2014-05-05

    Curcumin, main compound obtained from rizhoma of Curcuma longa, shows antitumoral, antioxidant, anticarcinogenic and gastric protective properties. Recently, it has been demonstrated that curcumin exerts its gastric protective action due to an increase in gastric nitric oxide (NO) levels. However, it is unknown whether these increased NO levels are associated with activation of intracellular signaling pathways. Thus, the purpose of this study was to investigate the role of NO-cGMP-KATP pathway in the gastric protective effect of curcumin during indomethacin-induced gastric injury in the rat. Adult female Wistar rats were gavaged with curcumin (3-300mg/kg, p.o.) or omeprazole (30mg/kg, p.o.) 30min before indomethacin insult (30mg/kg, p.o.). Other groups of rats were administered L-NAME (70mg/kg, i.p.; inhibitor of nitric oxide synthase), ODQ (10mg/kg, i.p.; inhibitor of soluble guanylate cyclase) or glibenclamide (1mg/kg, i.p.; blocker of ATP-sensitive potassium (KATP) channels) 30min before curcumin (30mg/kg, p.o.). 3h after indomethacin administration, rats were sacrificed and gastric injury was evaluated by determining total damaged area. A sample of gastric tissue was harvested and processed to quantify organic nitrite levels. Curcumin significantly protected against indomethacin-induced gastric injury and this effect was comparable to gastroprotective effect by omeprazole. L-NAME, ODQ and glibenclamide significantly prevented the curcumin-mediated gastric protective effect in the indomethacin-induced gastric injury model. Furthermore, curcumin administration induced a significant increase in gastric nitric oxide levels as compared to vehicle administration. Our results show for the first time that curcumin activates NO/cGMP/KATP pathway during its gastro protective action. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Polymer fraction of Aloe vera exhibits a protective activity on ethanol-induced gastric lesions.

    PubMed

    Park, Chul-Hong; Nam, Dong-Yoon; Son, Hyeong-U; Lee, Si-Rim; Lee, Hyun-Jin; Heo, Jin-Chul; Cha, Tae-Yang; Baek, Jin-Hong; Lee, Sang-Han

    2011-04-01

    For centuries, Aloe has been used as a herbal plant remedy against skin disorders, diabetes, and for its cardiac stimulatory activity. Here, we examined the gastroprotective effects of an Aloe vera polymer fraction (Avpf; molecular weight cut-off ≥50 kDa; 150 mg/kg body weight, p.o.) on an ethanol-induced gastric lesion mouse model. Mice pre-treated with Avpf had significantly fewer gastric lesions than their respective controls. To further examine the potential mechanism underlying this effect, we used reverse transcription-polymerase chain reaction to examine nitric oxide synthase and matrix metalloproteinase (MMP)mRNA expression on tissues from gastric lesions. Our results revealed that the mRNA expressions of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) were each reduced by ~50% in Avpf-treated mice vs. the controls, whereas, the mRNA expression levels of endothelial nitric oxide synthase remained unchanged. MMP-9, an index for gastric lesions, also alleviated the ethanol-treated gastric ulceration during Avpf treatment. These findings collectively suggest that Avpf significantly protects the gastric mucosa against ethanol-induced gastric damage, at least in part, by decreasing mRNA expression levels of not only iNOS and nNOS, but also MMP-9.

  13. Effect of Manilkara hexandra (Roxb.) Dubard against experimentally-induced gastric ulcers.

    PubMed

    Shah, Mamta B; Goswami, S S; Santani, D D

    2004-10-01

    Effects of the flavonoid rich fraction of the stem bark of Manilkara hexandra (Roxb.) Dubard, have been studied on ethanol, ethanol-indomethacin and pylorus ligated gastric ulcers in experimental animals. Oral administration of the ethyl acetate extract (extract A3) inhibited the formation of gastric lesions induced by ethanol in a dose dependent manner. The protective effect of extract A3 against ethanol induced gastric lesions was not abolished by pretreatment with indomethacin (10 mg kg(-1)). Further, extract A3 inhibited increase in vascular permeability due to ethanol administration. Extent of lipid peroxidation was significantly reduced in animals treated with extract. Extract A3 also inhibited the formation of gastric ulcers induced by pylorus ligation, when administered both orally and intraperitoneally. Moreover, pretreatment with extract A3 increased mucus production and glycoprotein content, which was evident from the rise in mucin activity and TC: PR ratio.

  14. Protective effects of polysaccharide from Dendrobium nobile against ethanol-induced gastric damage in rats.

    PubMed

    Zhang, Yi; Wang, Hongxin; Mei, Nana; Ma, Chaoyang; Lou, Zaixiang; Lv, Wenping; He, GuoHua

    2017-09-01

    Dendrobium nobile is a medicinal herb in traditional China and Southeast Asian countries. Employing a rat model of ethanol-induced gastric ulcer, we examined the protective effect of polysaccharide (JCP) extracted from Dendrobium nobile and explored the related mechanisms. Oral administration with 100mg/kg and 300mg/kg body weight JCP for days can significant prevent the formation of gastric ulcer. Moreover, JCP pretreatment could alleviate ethanol-induced histological damage, antioxidant activities, the level of epidermal growth factor, gastric concentration of prostaglandin E, and regulate the signaling pathways of mitogen-activated protein kinases and matrix metalloproteinases. This study investigated the ethanol-induced gastric ulcer protective effect of JCP for the first time, and elucidated that the protective mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Guarana (Paullinia cupana Mart.) offers protection against gastric lesions induced by ethanol and indomethacin in rats.

    PubMed

    Campos, A R; Barros, A I S; Santos, F A; Rao, V S N

    2003-12-01

    The effects of guarana (Paullinia cupana) extract were analyzed in rats on acute gastric lesions induced by ethanol and indomethacin and were compared to those produced by caffeine, a methylxanthine. Guarana (50 and 100 mg/kg p.o.) pretreated animals showed a significant reduction in the severity of gastric lesions induced by absolute ethanol in a manner similar to caffeine (20 and 30 mg/kg p.o.). Against indomethacin-induced gastric ulceration, guarana at a higher dose offered significant protection but caffeine was ineffective at the doses tested. In 4 h pylorus-ligated rats, both guarana and caffeine caused significant diminution in the gastric secretory volume as well as the total acidity. Gastrointestinal transit in mice was not significantly affected by either of these agents. These findings indicate that guarana has a gastroprotective property that needs further elucidation as regards to its mechanism. Copyright 2003 John Wiley & Sons, Ltd.

  16. [Preventive effects of teprenone on gastric mucosal lesions induced by Helicobacter pylori in mice].

    PubMed

    Yang, Gui-bin; Hu, Fu-lian; Mu, Fang-hong

    2006-04-11

    To determine the preventive effect of teprenone on gastric mucosal injury induced with Helicobacter pylori concentrated culture supernatant (CCS) in Balb/c mice. Gastric mucosa lesions were induced with intragastrical administration of Helicobacter pylori CCS. Sixty Balb/c mice were divided into control group, injury group, sucralfate protective group and teprenone protective group. Mice of two protective groups were pretreated with sucralfate or teprenone respectively before induction of gastric mucosa lesions. Mucosal changes were assessed by microscopic examination, quantitative histology and electron microscopy. Histologic and ultrastructural lesions in protective groups were less severe than those in injury group. Epithelial damage scoring (EDS) of teprenone protective group (1.68 +/- 0.69) and sucralfate protective group (1.72 +/- 0.73) were significantly decreased than injury group (2.47 +/- 0.58, P < 0.05). Teprenone as well as sucralfate reduces gastric mucosal lesions induced by Helicobacter pylori CCS in mice.

  17. Local opioid-sensitive afferent sensory neurones in the modulation of gastric damage induced by Paf.

    PubMed Central

    Esplugues, J. V.; Whittle, B. J.; Moncada, S.

    1989-01-01

    1. The role of local sensory neurones in modulating the extent of gastric mucosal damage induced by close-arterial infusion of platelet-activating factor (Paf 50 ng kg-1 min-1 for 10 min) has been investigated in the anaesthetized rat. 2. Local intra-arterial infusion of the neurotoxin, tetrodotoxin (TTX), substantially augmented the mucosal damage induced by Paf, as assessed by both macroscopic and histological techniques. 3. In rats pretreated with capsaicin 2 weeks prior to study, to induce a functional ablation of primary afferent neurones, gastric damage induced by Paf was significantly augmented. 4. Administration of morphine (0.75-3 mg kg-1 i.v.) or its peripherally acting quaternary analogue, N-methyl morphine (15 mg kg-1 i.v.), also significantly enhanced the gastric damage induced by Paf. 5. The potentiation by morphine of Paf-induced gastric damage was inhibited by administration of the opioid antagonists, naloxone (1 mg kg-1 i.v.) or the peripherally acting N-methyl nalorphine (3 mg kg-1 i.v.). 6. Administration of TTX or morphine alone, or pretreatment with capsaicin did not induce any detectable mucosal damage, suggesting that interference with local sensory neuronal activity itself does not directly induce mucosal disruption. 7. These results indicate that peripheral opiate-sensitive afferent sensory neurones play a physiological defensive role in the mucosa, attenuating the extent of gastric damage induced by Paf. PMID:2758231

  18. Effects of nitric oxide on gastric ulceration induced by nicotine and cold-restraint stress.

    PubMed

    Qui, Bo-Sheng; Mei, Qi-Bing; Liu, Li; Tchou-Wong, Kam-Meng

    2004-02-15

    Stress induces gastric ulceration in human and experimental animals. People tend to smoke more cigarettes when under stress. Nitric oxide (NO) and nicotine have opposing effects on gastric integrity. The present study examined the possible therapeutic benefit of NO in nicotine-treated rats with stress-induced gastric ulceration. Rats drank a nicotine solution while control rats drank tap water for 20 days. The alkoloid was then replaced by water with or without supplementation of isosorbide dinitrate (NO donor) for an additional 10 days. Isosorbide dinitrate was given twice shortly before experiments (acute) or three times daily by oral gavages for 10 days after the rats stopped drinking nicotine solution. At the end of experiments, ulcer index, gastric adhesion mucus content and MPO activity were measured and analysed. Nicotine treatment decreased gastric mucus content and intensified stress-induced gastric ulcer. A higher ulcer index persisted even after the rats stopped drinking nicotine solution for 10 days. Acute NO donor showed no benefit on both mucus and ulcer index in nicotine treatment or/and stress condition. Chronic NO donor treatment reversed the worsening action of nicotine in stomach. Stress increased gastric mucosal myeloperoxidase (MPO) activity, which was antagonized by chronic NO treatment. However, nicotine was unlikely to change mucosal MPO activity. The intensifying action of nicotine on stress-induced gastric ulceration persists for 10 days after cessation. Nicotine treatment significantly decreases gastric mucus content that can be restored by chronic NO donor treatment. The present study suggests that NO antagonizes the ulcerogenic action of nicotine through a cytoprotective way.

  19. Anti-inflammatory activity and gastric lesions induced by zinc-tenoxicam.

    PubMed

    Nascimento, Jorge Willian L; Santos, Luiz Henrique; Nothenberg, Michael S; Coelho, Márcio M; Oga, Seizi; Tagliati, Carlos A

    2003-06-01

    Oral administration of tenoxicam or zinc-tenoxicam complex inhibited to a similar extent carrageenin-induced paw oedema and granulomatous tissue formation in rats as well as the acetic acid induced writhing response in mice. Gastric lesions induced by oral administration of zinc-tenoxicam were reduced in number and severity when compared with those induced by tenoxicam or the co-administration of tenoxicam and zinc acetate. However, after intraperitoneal administration, both zinc-tenoxicam and tenoxicam plus zinc acetate induced a reduced number of gastric lesions as compared with tenoxicam.

  20. Inhibition of Oxidative Stress and Enhancement of Cellular Activity by Mushroom Lectins in Arsenic Induced Carcinogenesis.

    PubMed

    Rana, Tanmoy; Bera, Asit Kumar; Das, Subhashree; Bhattacharya, Debasis; Pan, Diganta; Das, Subrata Kumar

    2016-01-01

    Chronic arsenicosis is a major environmental health hazard throughout the world, including India. Animals and human beings are affected due to drinking of arsenic contaminated ground water, due to natural mineral deposits, arsenical pesticides or improperly disposed arsenical chemicals. Arsenic causes cancer with production of free radicals and reactive oxygen species (ROS) that are neutralized by an elaborate antioxidant defense system consisting of enzymes and numerous non-enzymatic antioxidants. Dietary antioxidant supplements are useful to counteract the carcinogenesis effects of arsenic. Oyster mushroom lectins can be regarded as ingredients of popular foods with biopharmaceutical properties. A variety of compounds have been isolated from mushrooms, which include polysaccharides and polysaccharopeptides with immune-enhancing effects. Lectins are beneficial in reducing arsenic toxicity due to anticarcinogenetic roles and may have therapeutic application in people suffering from chronic exposure to arsenic from natural sources, a global problem that is especially relevant to millions of people on the Indian subcontinent.

  1. Apigenin inhibits oxidative stress-induced macromolecular damage in N-nitrosodiethylamine (NDEA)-induced hepatocellular carcinogenesis in Wistar albino rats.

    PubMed

    Jeyabal, Prince Vijeya Singh; Syed, Mumtaz Banu; Venkataraman, Magesh; Sambandham, Jamuna Kumari; Sakthisekaran, Dhanapal

    2005-09-01

    Apigenin (4',5,7-trihydroxyflavone), a flavone subclass of flavonoid widely distributed in many herbs, fruits, and vegetables is a substantial component of the human diet and has been shown to possess a variety of biological activities including tumor growth inhibition and chemoprevention. Recent studies in several biological systems have shown that apigenin induces tumor growth inhibition, cell cycle arrest, and apoptosis. Free radical-induced degradation of polyunsaturated fatty acid results in electrophilic products and causes severe oxidative stress. Oxidative stress induced by free radicals, nonoxidizing species, electrophiles, and associated DNA damages have been frequently coupled with carcinogenesis. In the present study, the protective role of apigenin was examined against the oxidative stress caused by N-nitrosodiethylamine (NDEA) and phenobarbital (PB) in Wistar albino rats. Oxidative stress was measured in terms of lipid peroxidation (LPO) and protein carbonyl formation. Oxidative stress-induced DNA damage was measured by single cell gel electrophoresis (comet assay). Apigenin exhibited its antioxidant defense against NDEA-induced oxidative stress. We have observed minimal levels of LPO and DNA damage in apigenin-treated hepatoma bearing animals. Based on the results, we suggest that apigenin may be developed as a promising chemotherapeutic agent against the development of chemical carcinogenesis.

  2. Interaction with neutrophils promotes gastric cancer cell migration and invasion by inducing epithelial-mesenchymal transition.

    PubMed

    Zhang, Wen; Gu, Jianmei; Chen, Jingyan; Zhang, Peng; Ji, Runbi; Qian, Hui; Xu, Wenrong; Zhang, Xu

    2017-09-06

    Emerging evidence has revealed that neutrophils have phenotypic and functional plasticity. Neutrophils could be polarized towards a pro-tumor phenotype by tumor-derived factors. In the present study, we investigated the role of the interaction with neutrophils on the functions of gastric cancer cells in vitro. Human promyelocytic leukemia HL-60 cells were induced to differentiate into neutrophil-like cells (HL-60N) using dimethyl sulfoxide (DMSO). Human gastric cancer cells were co-cultured with HL-60N cells or treated with the conditioned medium (CM) of cancer-activated HL-60N cells. The migration and invasion of gastric cancer cells were significantly enhanced while their proliferation was minimally altered. The expression of pro-inflammatory factors including IL-6, IL-8, IL-1β, and TNFα was significantly increased in cancer-activated HL-60N cells, which induced the activation of the ERK pathway and epithelial-mesenchymal transition (EMT) in gastric cancer cells. Blocking the ERK pathway activation reversed the promoting effects of cancer-activated HL-60N cells on gastric cancer cell migration and invasion. In addition, mouse gastric cancer cell derived CM could also increase the expression of pro-inflammatory factors in mouse bone marrow neutrophils, which in turn enhanced the migration and invasion of mouse gastric cancer cells. Collectively, our findings revealed that the interaction with neutrophils promoted gastric cancer cell migration and invasion through the activation of the ERK pathway and the induction of EMT, indicating that neutrophils may play an important role in gastric cancer metastasis. Therefore, targeting neutrophil-cancer cell interaction may provide a new strategy for the treatment of gastric cancer.

  3. Chemo-immunotherapy induces tumor regression in a mouse model of spontaneous mammary carcinogenesis

    PubMed Central

    Carpinelli, Giulia; Canese, Rossella; Cecchetti, Serena; Schiavoni, Giovanna; D'Urso, Maria Teresa; Belardelli, Filippo; Proietti, Enrico

    2016-01-01

    Tumor-specific immune tolerance represents an obstacle for the development of effective anti-tumor immune responses through cancer vaccines. We here evaluated the efficacy of chemo-immunotherapy in breaking tumor-specific immune tolerance in an almost incurable mouse model of spontaneous carcinogenesis. Transgenic HER-2/neu mice bearing large mammary tumors received the adoptive transfer of splenocytes and serum isolated from immune donors, with or without pre-conditioning with cyclophosphamide. Treatment efficacy was assessed by monitoring tumor growth by manual inspection and by magnetic resonance imaging. The same chemo-immunotherapy protocol was tested on tumor-free HER-2/neu mice, to evaluate the effects on tumor emergence. Our data show that chemo-immunotherapy hampered carcinogenesis and caused the regression of large mammary tumor lesions in tumor-bearing HER-2/neu mice. The complete eradication of a significant number of tumor lesions occurred only in mice receiving cyclophosphamide shortly before immunotherapy, and was associated with increased serum anti HER-2/p185 antibodies and tumor leukocyte infiltration. The same protocol significantly delayed the appearance of mammary tumors when administered to tumor-free HER-2/neu mice, indicating that this chemo-immunotherapy approach acted through the elicitation of an effective anti-tumor immune response. Overall, our data support the immune-modulatory role of chemotherapy in overcoming cancer immune tolerance when administered at lymphodepleting non-myeloablative doses shortly before transfer of antigen-specific immune cells and immunoglobulins. These findings open new perspectives on combining immune-modulatory chemotherapy and immunotherapy to overcome immune tolerance in cancer patients. PMID:27486759

  4. Enhanced UV-induced skin carcinogenesis in transgenic mice overexpressing proprotein convertases.

    PubMed

    Fu, Jian; Bassi, Daniel E; Zhang, Jirong; Li, Tianyu; Cai, Kathy Q; Testa, Courtney Lyons; Nicolas, Emmanuelle; Klein-Szanto, Andres J

    2013-02-01

    The proprotein convertases (PCs) furin and PACE4 process numerous substrates involved in tumor growth, invasion, and metastasis. We have previously shown that PCs increase the susceptibility to chemical skin carcinogenesis. Because of the human relevancy of UV radiation in the etiopathogenesis of human skin cancer, we investigated whether or not transgenic mice overexpressing either furin alone or both furin and PACE4 show increased susceptibility to UV carcinogenesis. After backcrossing our previously described furin and PACE4 transgenic lines, targeted to the epidermis, into a SKH-1 background, we exposed both single and double transgenic mice to UV radiation for 34 weeks. The results showed an increase in squamous cell carcinoma (SCC) multiplicity of approximately 70% in the single furin transgenic mouse line SF47 (P < .002) and a 30% increase in the other single transgenic line SF49 when compared to wild-type (WT) SKH-1 mice. Interestingly, there was also an increase in the percentage of high histologic grade SCCs in the transgenic lines compared to the WT mice, i.e., WT = 9%, SF47 = 15%, and SF49 = 26% (P < .02). Targeting both furin and PACE4 to the epidermis in double transgenic mice did not have an additive effect on tumor incidence/multiplicity but did enhance the tumor histopathologic grade, i.e., a significant increase in higher grade SCCs was seen in the bigenic mouse line SPF47 (P < .02). Thus, we observed an increased susceptibility to UV in single furin transgenic mice that was not substantially enhanced in the double furin/PACE4 transgenic mice.

  5. Beyond gastric acid reduction: Proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells

    SciTech Connect

    Becker, Jan C. . E-mail: beckeja@uni-muenster.de; Grosser, Nina; Waltke, Christian; Schulz, Stephanie; Erdmann, Kati; Domschke, Wolfram; Schroeder, Henning; Pohle, Thorsten

    2006-07-07

    Proton pump inhibitors (PPIs) have been demonstrated to prevent gastric mucosal injury by mechanisms independent of acid inhibition. Here we demonstrate that both omeprazole and lansoprazole protect human gastric epithelial and endothelial cells against oxidative stress. This effect was abrogated in the presence of the heme oxygenase-1 (HO-1) inhibitor ZnBG. Exposure to either PPI resulted in a strong induction of HO-1 expression on mRNA and protein level, and led to an increased activity of this enzyme. Expression of cyclooxygenase isoforms 1 and 2 remained unaffected, and COX-inhibitors did not antagonize HO-1 induction by PPIs. Our results suggest that the antioxidant defense protein HO-1 is a target of PPIs in both endothelial and gastric epithelial cells. HO-1 induction might account for the gastroprotective effects of PPIs independently of acid inhibition, especially in NSAID gastropathy. Moreover, our findings provide additional perspectives for a possible but yet unexplored use of PPIs in vasoprotection.

  6. Effect of capsaicin and cimetidine on the healing of acetic acid induced gastric ulceration in the rat.

    PubMed Central

    Kang, J Y; Teng, C H; Chen, F C

    1996-01-01

    BACKGROUND: Capsaicin protects the gastric mucosa against experimental injury while capsaicin desensitisation reduces the rate of gastric ulcer healing. The effect of exogenous capsaicin on gastric ulcer healing has not to date been reported. AIM/METHOD: To investigate the effect of capsaicin, cimetidine, and in combination, given intragastrically in the healing of acetic acid induced chronic gastric ulcer in the rat. Treatment started immediately after ulcer induction. RESULTS: At the end of one week, capsaicin, cimetidine, and in combination increased ulcer healing but the effect of combined treatment was less than that of capsaicin alone. In an in vivo gastric chamber preparation, capsaicin increased, while cimetidine decreased, gastric mucosal blood flow measured by laser Doppler flowmetry. A dose response effect in reduction of gastric mucosal blood flow could be demonstrated for cimetidine. The gastric hyperaemic effect of capsaicin was blunted by prior administration of cimetidine. In contrast, capsaicin had no effect on gastric acid secretion and its addition to cimetidine did not affect the acid suppressant effect of the latter. CONCLUSIONS: Capsaicin promotes the healing of acetic acid induced gastric ulcer, probably by its gastric hyperaemic effect. Although cimetidine also promotes ulcer healing due to its inhibitory effect on acid secretion it may have an antagonistic effect on the gastric ulcer healing effect of capsaicin by virtue of inhibition of gastric hyperaemia. PMID:8984019

  7. Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis.

    PubMed

    Hawthorne, A B; Mahida, Y R; Cole, A T; Hawkey, C J

    1991-07-01

    1. Gastric damage induced by low-dose aspirin and the protective effect of enteric-coating was assessed in healthy volunteers in a double-blind placebo-controlled cross-over trial using Latin square design. Each was administered placebo, plain aspirin 300 mg daily, plain aspirin 600 mg four times daily, enteric-coated aspirin 300 mg daily, or enteric-coated aspirin 600 mg four times daily for 5 days. Gastric damage was assessed endoscopically, and gastric mucosal bleeding measured. 2. Aspirin 300 mg daily and 600 mg four times daily caused significant increases in gastric injury compared with placebo. Gastric mucosal bleeding was significantly more with the high dose, with a trend towards increased gastric erosions, compared with the low dose. 3. Enteric-coating of aspirin eliminated the injury caused by low dose aspirin and substantially reduced that caused by the higher dose. 4. All dosages and formulations caused similar inhibition of gastric mucosal prostaglandin E2 synthesis. 5. Serum thromboxane levels were suppressed equally with plain and enteric-coated aspirin. 6. In this short-term study in healthy volunteers, gastric toxicity from aspirin was largely topical, independent of inhibition of prostaglandin synthesis, and could be virtually eliminated by the use of an enteric-coated preparation.

  8. [The modifying effect of long-term administration of ascorbic acid with drinking water on asbestos-induced pleural carcinogenesis in Wistar rats].

    PubMed

    Stadnikova, N M; Vasil'eva, L A; Shelepov, V P; Pylev, L N

    1996-01-01

    Ascorbic acid administered with drinking water, in a concentration of 2.5%, together with sucrose (1%) was found to significantly inhibit the development of mesothelial and pleural tumors induced in Wistar rats by asbestos treatment. Said agents, however, failed to influence spontaneous carcinogenesis.

  9. Dietary feeding of Opuntia humifusa inhibits UVB radiation-induced carcinogenesis by reducing inflammation and proliferation in hairless mouse model.

    PubMed

    Lee, Jin-A; Jung, Bock-Gie; Kim, Tae-Hoon; Lee, Su-Gil; Park, Young-Seok; Lee, Bong-Joo

    2013-01-01

    It has been validated that ultraviolet B (UVB) irradiation induced both squamous and basal cell carcinomas, as a tumor initiator and promoter. Opuntia humifusa is a member of the Cactaceae family which has been demonstrated in our previous study to have a chemopreventive effect in 7, 12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate induced skin carcinogenesis models. Therefore, this study was designed to determine the protective effects of O. humifusa against photocarcinogenesis. O. humifusa was administrated to mice as a dietary feeding, following exposure to UVB radiation (180 mJ/cm(2)) twice a week of 30 weeks for skin tumor development in hairless mice. Dietary O. humifusa inhibited UVB-induced epidermal hyperplasia, infiltration of leukocytes, level of myeloperoxidase and the levels of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), in UVB exposed skin. Also, O. humifusa significantly inhibited both protein and mRNA expression level of cyclooxygenase-2 (COX-2), nitric oxide synthase (iNOS), proliferating cell nuclear antigen (PCNA) and cyclin D1 compared to the non-O. humifusa treated group. Collectively, these results suggest that O. humifusa could inhibit photocarcinogenesis in mouse skin and that protective effect is associated with the inhibition of not only UVB-induced inflammatory responses involving COX-2, iNOS and proinflammatory cytokines, but also the down-regulation of UVB-induced cellular proliferation. © 2013 The American Society of Photobiology.

  10. Membrane fluidity and surface changes during initiation of 1,2 dimethylhydrazine-induced colon carcinogenesis: protection by zinc.

    PubMed

    Chadha, Vijayta Dani; Dhawan, D K

    2009-01-01

    The present study evaluated the modulatory effects of zinc on colonic membrane fluidity and surface abnormalities following 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis. Rats were segregated into four groups: normal control, DMH treated, zinc treated, DMH + zinc treated. Colon carcinogenesis was initiated through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 8 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227 mg/L in drinking water, ad libitum, for the entire duration of the study. Brush border membranes (BBM) were isolated from the colon of rats and the fluidity parameters were assessed by steady-state fluorescence polarization technique using the membrane extrinsic fluorophore 1,6-diphenyl-1,3,5-hexatriene (DPH). The translational diffusion was measured by using the excimer formation of pyrene incorporated in the membrane. The results demonstrated a significant increase in the polarization and anisotropy, accompanied by an increase in order parameter in the membrane preparations from the colon of DMH-injected rats. Further, studies with pyrene fluorophore indicated a marked decrease in membrane microviscosity following DMH treatment. However, the alterations in membrane fluorescence polarization and the fluidity parameters were completely restored following zinc treatment. Drastic alterations in colon surface were noticed after 8 weeks of DMH treatment. However, zinc treatment to DMH-treated rats greatly restored normalcy in the colonic surface. The study concludes that zinc has a strong membrane stabilizing effect and thus has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats.

  11. Elimination of deleterious effects of DMBA-induced skin carcinogenesis in mice by Syzygium cumini seed extract.

    PubMed

    Parmar, Jyoti; Sharma, Priyanka; Verma, Preeti; Sharma, Priyanka; Goyal, Pradeep K

    2011-09-01

    The inhibition of tumor incidence by hydro-alcoholic extract of S.cumini seed was evaluated in mice on two stage process of skin carcinogenesis induced by single application of 7, 12-dimethyl benz(a)anthracene (100 µg/100µl of acetone), and 2 weeks later promoted by repeated application of croton oil (1% acetone/thrice in a week) till the end of the experiment (i.e. 16 weeks). Oral administration of extract at a dose of 250mg/kg b.wt./day at the peri-initiational stage (i.e. 7 days before and 7 days after DMBA application), promotional stage (i.e. from the time of croton oil application) and at both the stages (i.e. 7 days prior to DMBA application & continued till the end of experiment) to the mice, recorded a significant reduction in tumor incidence to 37.5, 50 & 25% respectively in comparison to the carcinogen treated control, where tumor incidence was found as 100%. Tumor yield and Tumor burden were also significantly reduced by SCE. Similarly, the cumulative number of papillomas after 16 weeks was 68 in the control group, which was reduced to 15, 21 & 8 in the animals treated with the SCE continuously at peri-, post- and peri- & post- initiation stage respectively. A significant impairment was noticed in the levels of reduced glutathione, superoxide dismutase, catalase & protein and enhancement in LPO in liver and skin of carcinogen treated control mice as compared with vehicle treated mice. All such parameters were returned to near normal value by administration of SCE to DMBA treated mice. These results suggest a possible chemopreventive property of S.cumini against DMBA induced skin carcinogenesis in mice.

  12. Comparative evaluation of antiproliferative, antiangiogenic and apoptosis inducing potential of black tea polyphenols in the hamster buccal pouch carcinogenesis model

    PubMed Central

    Letchoumy, Paramasivame Vidjaya; Mohan, Kurapathy Venkata Poorna Chandra; Prathiba, Duvuru; Hara, Yukihiko; Nagini, Siddavaram

    2007-01-01

    Background To evaluate the relative chemopreventive efficacy of two black tea polyphenols, Polyphenon-B [P-B] and BTF-35 on 7,12-dimethylbenz [a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Methods Hamsters were divided into 6 groups. The right buccal pouches of animals in groups 1–3 were painted with 0.5% of DMBA three times a week for 14 weeks. While hamsters in group 1 received no further treatment, animals in groups 2 and 3 received diet containing 0.05% P-B and BTF-35 respectively, four weeks before DMBA painting that was continued until the end of the experiments. Animals in groups 4 and 5 were given P-B and BTF-35 alone respectively as in groups 2 and 3. Group 6 animals served as the untreated control. All the animals were sacrificed after 18 weeks. The expression of p21, cyclin D1, glutathione S-transferase pi (GST-P), nuclear factor kappa B (NF-κB), Bcl-2, Bax, cytochrome C, caspase-3, caspase-9, poly(ADP-ribose) polymerase (PARP), cytokeratins and vascular endothelial growth factor (VEGF) was analysed by RT-PCR, immunohistochemical and Western blot analyses. Results DMBA treated animals developed buccal pouch carcinomas that displayed increased expression of p21, cyclin D1, GST-P, NF-κB, cytokeratins, VEGF and Bcl-2 with decreased expression of Bax, cytochrome C, caspase-3, caspase-9, and PARP. Dietary administration of both P-B and BTF-35 reduced the incidence of DMBA-induced HBP carcinomas by modulating markers of cell proliferation, cell survival, tumour infiltration, angiogenesis, and apoptosis. Conclusion The results of the present study provide a mechanistic basis for the chemopreventive potential of black tea polyphenols. The greater efficacy of BTF-35 in inhibiting HBP carcinogenesis and modulating multiple molecular targets may have a potential role in the prevention of oral cancer. PMID:18053169

  13. Teprenone promotes the healing of acetic acid-induced chronic gastric ulcers in rats by inhibiting neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues.

    PubMed

    Kobayashi, T; Ohta, Y; Yoshino, J; Nakazawa, S

    2001-01-01

    Teprenone, an anti-ulcer drug, has been reported to promote the healing of acetic acid-induced chronic gastric ulcers in rats by stimulating gastric mucus synthesis and secretion. Recently, it has been implicated that neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues have an inhibitory effect on the healing of acetic acid-induced chronic gastric ulcers in rats. Therefore, we attempted to clarify whether teprenone exerts a healing-promoting effect on acetic acid-induced chronic gastric ulcers through its inhibitory effect on neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues. In rats with chronic gastric ulcers made by applying acetic acid to the stomach, gastric ulcer healing started later than 3 days after the acetic acid application. Gastric mucosal myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration, and lipid peroxide content were higher in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application. Gastric mucosal non-protein SH content was lower in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application, and gastric mucosal adherent mucus content was lower in the ulcerated region than in the intact region on the 8th and 15th day. Daily oral administration of teprenone (100 mg kg(-1)x 2) for 7 or 14 days, starting on the 8th day after the application of acetic acid to the stomach, enhanced the reduction of the ulcer area with attenuation of all these biochemical changes found in the ulcerated region. The teprenone administration caused a decrease in MPO activity and an increase in adherent mucus content in the gastric mucosa of the intact region. These results suggest that the healing-promoting effect of teprenone on acetic acid-induced chronic gastric ulcers in rats could be due not only to stimulation of gastric mucus secretion but also to inhibition of neutrophil infiltration

  14. Oral glutathione supplementation drastically reduces Helicobacter-induced gastric pathologies

    PubMed Central

    De Bruyne, Ellen; Ducatelle, Richard; Foss, Dennis; Sanchez, Margaret; Joosten, Myrthe; Zhang, Guangzhi; Smet, Annemieke; Pasmans, Frank; Haesebrouck, Freddy; Flahou, Bram

    2016-01-01

    Helicobacter (H.) suis causes gastric pathologies in both pigs and humans. Very little is known on the metabolism of this bacterium and its impact on the host. In this study, we have revealed the importance of the glutamate-generating metabolism, as shown by a complete depletion of glutamine (Gln) in the medium during H. suis culture. Besides Gln, H. suis can also convert glutathione (GSH) to glutamate, and both reactions are catalyzed by the H. suis γ-glutamyltranspeptidase (GGT). Both for H. pylori and H. suis, it has been hypothesized that the degradation of Gln and GSH may lead to a deficiency for the host, possibly initiating or promoting several pathologies. Therefore the in vivo effect of oral supplementation with Gln and GSH was assessed. Oral supplementation with Gln was shown to temper H. suis induced gastritis and epithelial (hyper)proliferation in Mongolian gerbils. Astonishingly, supplementation of the feed with GSH, another GGT substrate, resulted in inflammation and epithelial proliferation levels returning to baseline levels of uninfected controls. This indicates that Gln and GSH supplementation may help reducing tissue damage caused by Helicobacter infection in both humans and pigs, highlighting their potential as a supportive therapy during and after Helicobacter eradication therapy. PMID:26833404

  15. Syzygium aromaticum water extract attenuates ethanol‑induced gastric injury through antioxidant effects in rats.

    PubMed

    Jin, Seong Eun; Lee, Mee-Young; Shin, In-Sik; Jeon, Woo-Young; Ha, Hyekyung

    2016-07-01

    The aim of the present study was to investigate whether Syzygium aromaticum water extract (SAWE) has a protective effect against ethanol‑induced gastric injury in rats. Acute gastric injury was induced via intragastric administration of absolute ethanol at a dose of 5 ml/kg. SAWE (250 or 500 mg/kg/day) or cimetidine (100 mg/kg/day), which was used as a positive control, were administered to the rats 2 h prior to ethanol administration for 3 days. All rats were sacrificed 24 h following the final ethanol administration. To examine whether SAWE has a gastroprotective effect, assays were performed to assess the contents of malondialdehyde (MDA) and glutathione (GSH), the activities of catalase, glutathione‑S‑transferase and superoxide dismutase, and an immune-linked immunosorbent assay was performed for prostaglandin E2 (PGE2) production in gastric tissues by hematoxylin and eosin and periodic acid-Schiff staining. Histological assessment of the gastric wall was performed. Compared with ethanol treatment alone, treatment with SAWE at a dose of 250 mg/kg/day significantly decreased the gastric MDA content and increased the GSH content, catalase activity, and production of gastric PGE2. Histological assessment showed that SAWE attenuated inflammatory cell infiltration and the loss of epithelial cells. These findings suggested that SAWE protected against ethanol‑induced gastric mucosal injury in the rats. These effects appeared to be associated with antioxidant activity, activation of the production of PGE2, suppression of inflammatory cell infiltration and loss of epithelial cells in the gastric mucosa. Collectively, SAWE may be beneficial in the prevention of gastric disease associated to oxidative stress.

  16. Role of mucus in ischemia/reperfusion-induced gastric mucosal injury in rats.

    PubMed

    Mojzis, J; Hegedüsová, R; Mirossay, L

    2000-01-01

    Gastric mucus plays an important role in gastric mucosal protection. Apart from its "barrier" function, it has been demonstrated that mucus protects gastric epithelial cells against toxic oxygen metabolites derived from the xanthine/ xanthine oxidase system. In this study, we investigated the effect of malotilate and sucralfate (mucus production stimulators) and N-acetylcysteine (mucolytic agent) on ischemia/reperfusion-induced gastric mucosal injury. Gastric ischemia was induced by 30 min clamping of the coeliac artery followed by 30 min of reperfusion. The mucus content was determined by the Alcian blue method. Sucralfate (100 mg/kg), malotilate (100 mg/kg), and N-acetylcysteine (100 mg/kg) were given orally 30 min before surgery. Both sucralfate and malotilate increased the mucus production in control rats. On the other hand, N-acetyloysteine significantly decreased mucus content in control (sham) group. A significant decrease of mucus content was found in the control and the N-acetylcysteine pretreated group during the period of ischemia. On the other hand, sucralfate and malotilate prevented the decrease the content of mucus during ischemia. A similar result can be seen after ischemia/reperfusion. In the control group and N-acetylcysteine pretreated group a significant decrease of adherent mucus content was found. However, sucralfate and malotilate increased mucus production (sucralfate significantly). Sucralfate and malotilate also significantly protected the gastric mucosa against ischemia/reperfusion-induced injury. However, N-acetylcysteine significantly increased gastric mucosal injury after ischemia/reperfusion. These results suggest that gastric mucus may be involved in the protection of gastric mucosa after ischemia/reperfusion.

  17. Gastroprotective effect of Cymbopogon citratus infusion on acute ethanol-induced gastric lesions in rats.

    PubMed

    Sagradas, Joana; Costa, Gustavo; Figueirinha, Artur; Castel-Branco, Maria Margarida; Silvério Cabrita, António Manuel; Figueiredo, Isabel Vitória; Batista, Maria Teresa

    2015-09-15

    Treatment of gastric ulcers with medicinal plants is quite common in traditional medicine worldwide. Cymbopogon citratus (DC) Stapf. leaves infusion has been used in folk medicine of many tropical and subtropical regions to treat gastric disturbances. The aim of this study was to assess the potential gastroprotective activity of an essential oil-free infusion from C. citratus leaves in acute gastric lesions induced by ethanol in rat. The study was performed on adult male Wistar rats (234.0±22.7g) fasted for 24h but with free access to water. The extract was given orally before (prevention) or after (treatment) intragastric administration of absolute ethanol. Effects of dose (28 or 56mg/kg of body weight) and time of contact of the extract with gastric mucosa (1 or 2h) were also assessed. Animals were sacrificed, being the stomachs removed and the lesions were assessed by macroscopic observation and histopathology. C. citratus extract, given orally before or after ethanol, significantly (P<0.01) reduced gastric mucosal injury compared with control group (vehicle+ethanol). The effect does not appear to be dose-dependent. Results also suggested that the extract is more effective when the time of contact with gastric mucosa increases. The results of this assay confirm the gastroprotective activity of C. citratus extract on experimental gastric lesions induced by ethanol, contributing for the pharmacological validation of its traditional use. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Effect of diallyl disulfide on acute gastric mucosal damage induced by alcohol in rats.

    PubMed

    Lee, I-C; Baek, H-S; Kim, S-H; Moon, C; Park, S-H; Kim, S-H; Shin, I-S; Park, S-C; Kim, J-C

    2015-03-01

    This study investigated the gastroprotective effects of diallyl disulfide (DADS), a secondary organosulfur compound derived from garlic (Allium sativum L.) on experimental model of ethanol (EtOH)-induced gastric ulcer in rats. The antiulcerogenic activity of DADS was evaluated by gross/histopathological inspection, pro-inflammatory cytokines, and lipid peroxidation with antioxidant enzyme activities in the stomach. DADS (100 mg/kg) was administered by oral gavage 2 h prior to EtOH treatment (5 ml/kg). The animals were killed 1 h after receiving EtOH treatment. Pretreatment with DADS attenuated EtOH-induced gastric mucosal injury, as evidenced by decreased severity of hemorrhagic lesions and gastric ulcer index upon visual inspection. DADS also prevented histopathological alterations and gastric apoptotic changes caused by EtOH. An increase in tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase was observed in the gastric tissues of EtOH-treated rats that coincided with increased serum TNF-α and interleukin 6 levels. In contrast, DADS effectively suppressed production of pro-inflammatory mediators induced by EtOH. Furthermore, DADS prevented the formation of gastric malondialdehyde and the depletion of reduced glutathione content and restored antioxidant enzyme activities, such as catalase, glutathione peroxidase, and glutathione reductase in the gastric tissues of EtOH-treated rats. These results indicate that DADS prevents gastric mucosal damage induced by acute EtOH administration in rats and that the protective effects of DADS may be due to its potent antioxidant and anti-inflammatory activities. © The Author(s) 2015.

  19. Role of mucus in gastric mucosal injury induced by local ischemia/reperfusion.

    PubMed

    Seno, K; Joh, T; Yokoyama, Y; Itoh, M

    1995-09-01

    The role of gastric mucus was evaluated in a rat model of gastric epithelial damage induced by local ischemia/reperfusion (I/R) stress. In this model, blood-to-lumen chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) clearance served as an index of injury. Tetraprenyl acetone (TPA; 100 mg, 200 mg/kg IP) was used to stimulate mucus production. Administration of TPA increased both the hexosamine content in gastric tissue and the amount of alcian blue-periodic acid Schiff (AB-PAS) stained mucus in the mucosa in a dose-dependent manner. Increases in 51Cr-EDTA clearance induced by I/R were significantly attenuated by TPA in a dose-dependent manner. N-acetyl-L-cysteine (NAC; 0.6%, 0.8%) was perfused into the gastric lumen to assess the effect of reduction in mucus on the injury induced by I/R. Although mean values of hexosamine content were increased by perfusion with NAC, AB-PAS-stained mucus in the mucosa was significantly decreased in a dose-dependent manner. Perfusion of NAC did not change basal 51Cr-EDTA clearance but significantly exacerbated the increase in clearance induced by I/R in a dose-dependent manner. These results indicate that gastric mucus protects the gastric mucosa against I/R stress in vivo.

  20. Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice

    SciTech Connect

    Li, Weifeng Huang, Huimin; Niu, Xiaofeng Fan, Ting; Mu, Qingli; Li, Huani

    2013-10-01

    Excessive alcohol consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 ml/100 g) were pre-treated with THC (10 or 20 mg/kg, ip), cimetidine (100 mg/kg, ip) or saline in different experimental sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increased pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO production and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression. - Highlights: • THC decreased ethanol-induced pro-inflammatory cytokine release. • THC inhibited the production of NO in serum and gastric tissue. • THC reduced NF-κB expression and MPO accumulation in ethanol-induced gastric tissue.

  1. Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice.

    PubMed

    Zhang, Yanqiao; Ge, Xuemei; Heemstra, Lydia A; Chen, Wei-Dong; Xu, Jiesi; Smith, Joseph L; Ma, Huiyan; Kasim, Neda; Edwards, Peter A; Novak, Colleen M

    2012-02-01

    Farnesoid X receptor (FXR) is known to play important regulatory roles in bile acid, lipid, and carbohydrate metabolism. Aged (>12 months old) Fxr(-/-) mice also develop spontaneous liver carcinomas. In this report, we used three mouse models to investigate the role of FXR deficiency in obesity. As compared with low-density lipoprotein receptor (Ldlr) knockout (Ldlr(-/-)) mice, the Ldlr(-/-)Fxr(-/-) double-knockout mice were highly resistant to diet-induced obesity, which was associated with increased expression of genes involved in energy metabolism in the skeletal muscle and brown adipose tissue. Such a striking effect of FXR deficiency on obesity on an Ldlr(-/-) background led us to investigate whether FXR deficiency alone is sufficient to affect obesity. As compared with wild-type mice, Fxr(-/-) mice showed resistance to diet-induced weight gain. Interestingly, only female Fxr(-/-) mice showed significant resistance to diet-induced obesity, which was accompanied by increased energy expenditure in these mice. Finally, we determined the effect of FXR deficiency on obesity in a genetically obese and diabetic mouse model. We generated ob(-/-)Fxr(-/-) mice that were deficient in both Leptin and Fxr. On a chow diet, ob(-/-)Fxr(-/-) mice gained less body weight and had reduced body fat mass as compared with ob/ob mice. In addition, we observed liver carcinomas in 43% of young (<11 months old) Ob(-/-)Fxr(-/-) mice. Together these data indicate that loss of FXR prevents diet-induced or genetic obesity and accelerates liver carcinogenesis under diabetic conditions.

  2. Effects of gastric vagotomy on visceral cell proliferation induced by ventromedial hypothalamic lesions: role of vagal hyperactivity.

    PubMed

    Kintaka, Yuri; Osaka, Toshimasa; Suzuki, Yoko; Hashiguchi, Takeo; Niijima, Akira; Kageyama, Haruaki; Fumiko, Takenoya; Shioda, Seiji; Inoue, Shuji

    2009-07-01

    In rats, ventromedial hypothalamic (VMH) lesions induce cell proliferation in the visceral organs (stomach, small intestine, liver, and pancreas) due to hyperactivity of the vagus nerve. To investigate the effects of selective gastric vagotomy on VMH lesion-induced cell proliferation and secretion of gastric acid, we assessed the mitotic index (the number of proliferating cell nuclear antigen (PCNA)-immunopositive cells per 1,000 cells in the gastric mucosal cell layer) and measured the volume of secreted basal gastric acid. Furthermore, to explore whether or not ethanol-induced acute gastric mucosal lesions (AGML) lead to ulcer formation in VMH-lesioned rats, we assessed the ulcer index of both sham-operated and VMH-lesioned rats after administration of ethanol. VMH lesions resulted in an increased mitotic index and thickness of the gastric mucosal cell layer and gave rise to the hypersecretion of gastric acid. Selective gastric vagotomy restored these parameters to normal without affecting cell proliferation in other visceral organs. Ethanol-induced AGML caused ulcers in sham VMH-lesioned rats, whereas VMH-lesioned rats were less likely to exhibit such ulcers. These results suggest that VMH lesion-induced vagally mediated cell proliferation in the visceral organs is associated with hyperfunction in these organs, and VMH lesion-induced resistance to ethanol may be due to thickening of the gastric mucosal cell layer resulting from cell proliferation in the gastric mucosa-this in turn is due to hyperactivity of the vagus nerve.

  3. Use of dimethicone to reduce the fall in gastric potential difference induced by bile salts.

    PubMed

    Bergmann, J F; Simoneau, G; Chantelair, G; Caulin, C; Segrestaa, J M

    1989-01-01

    The gastric potential difference (PD) was measured in ten healthy volunteers after sodium taurocholate intake. This bile salt was given after treatment with dimethicone or placebo in a cross-over design study. With dimethicone the fall in PD was lower (16.1 vs. 24.8 mV,) and shorter (32.5 vs. 51.0 min) than with the placebo. Our result suggests that the silicone can prevent the formation of the gastric lesions induced by bile salts.

  4. Modeling Murine Gastric Metaplasia Through Tamoxifen-Induced Acute Parietal Cell Loss

    PubMed Central

    Saenz, Jose B.; Burclaff, Joseph; Mills, Jason C.

    2016-01-01

    Parietal cell loss represents the initial step in the sequential progression toward gastric adenocarcinoma. In the setting of chronic inflammation, the expansion of the mucosal response to parietal cell loss characterizes a crucial transition en route to gastric dysplasia. Here, we detail methods for using the selective estrogen receptor modulator tamoxifen as a novel tool to rapidly and reversibly induce parietal cell loss in mice in order to study the mechanisms that underlie these pre-neoplastic events. PMID:27246044

  5. Anticarcinogenic efficacy of phytic acid extracted from rice bran on azoxymethane-induced colon carcinogenesis in rats.

    PubMed

    Norazalina, S; Norhaizan, M E; Hairuszah, I; Norashareena, M S

    2010-05-01

    This study is carried out to determine the potential of phytic acid extracted from rice bran in the suppression of colon carcinogenesis induced by azoxymethane (AOM) in rats. Seventy-two male Sprague-Dawley rats were divided into 6 groups with 12 rats in each group. The intended rats for cancer treatment received two intraperitoneal injections of AOM in saline (15mg/kg bodyweight) over a 2-week period. The treatments of phytic acid were given in two concentrations: 0.2% (w/v) and 0.5% (w/v) during the post-initiation phase of carcinogenesis phase via drinking water. The colons of the animals were analyzed for detection and quantification of aberrant crypt foci (ACF) after 8 weeks of treatment. The finding showed treatment with 0.2% (w/v) extract phytic acid (EPA) gave the greatest reduction in the formation of ACF. In addition, phytic acid significantly suppressed the number of ACF in the distal, middle and proximal colon as compared to AOM alone (p<0.05). For the histological classification of ACF, treatment with 0.5% (w/v) commercial phytic acid (CPA) had the highest percentage (71%) of non-dysplastic ACF followed by treatment with 0.2% (w/v) EPA (61%). Administration of phytic acid also reduced the incidence and multiplicity of total tumors even though there were no significant differences between groups. In conclusion, this study found the potential value of phytic acid extracted from rice bran in reducing colon cancer risk in rats.

  6. Suppressive effects of Moringa oleifera Lam pod against mouse colon carcinogenesis induced by azoxymethane and dextran sodium sulfate.

    PubMed

    Budda, Sirintip; Butryee, Chaniphun; Tuntipopipat, Siriporn; Rungsipipat, Anudep; Wangnaithum, Supradit; Lee, Jeong-Sang; Kupradinun, Piengchai

    2011-01-01

    Moringa oleifera Lam (horseradish tree; tender pod or fruits) is a major ingredient in Thai cuisine and has some medicinal properties. Previous studies have shown potentially antioxidant, antitumor promoter, anticlastogen and anticarcinogen activities both in vitro and in vivo. The present study was conducted to investigate chemopreventive effects on azoxymethane (AOM)-initiated and dextran sodium sulfate (DSS)-promoted colon carcinogenesis in mice. Male ICR mice were divided into 8 groups: Group 1 served as a negative control; Group 2 received AOM/DSS as a positive control; Groups 3-5 were fed boiled freeze-dried M. oleifera (bMO) at 1.5%, 3.0% and 6.0%, respectively supplemented in basal diets for 5 weeks; Groups 6-8 were fed with bMO diets at the designed doses above for 2 weeks prior to AOM, during and 1 week after DSS administration. At the end of the study, colon samples were processed for histopathological examination. PCNA indices, and iNOS and COX-2 expression were assessed by immunohistochemistry. The results demonstrated the incidences and multiplicities of tumors in Groups 6-8 to be decreased when compared to Group 2 in a dose dependent manner, but this was significant only in Group 8. The PCNA index was also significantly decreased in Group 8 whereas iNOS and COX-2 protein expression were significantly decreased in Groups 7 and 8. The findings suggest that M. oleifera Lam pod exerts suppressive effects in a colitis-related colon carcinogenesis model induced by AOM/DSS and could serve as a chemopreventive agent.

  7. Prophylactic effects of Clausena excavata Burum. f. leaf extract in ethanol-induced gastric ulcers

    PubMed Central

    Albaayit, Shaymaa Fadhel Abbas; Abba, Yusuf; Abdullah, Rasedee; Abdullah, Noorlidah

    2016-01-01

    Clausena excavata is a natural herb with both antioxidant and anti-inflammatory properties. It has been used for decades in folkloric practice for the amelioration of various ailments. In this study, the gastroprotective activity of methanolic extract of C. excavata leaves (MECE) was determined in the Sprague Dawley rat ethanol-induced gastric ulcer model. Rats were pretreated with a single dose of vehicle (5% Tween 20), 20 mg/mL omeprazole, 400 and 200 mg/mL of MECE dissolved in 5% Tween 20. Ulcer was induced with 5 mL/kg of ethanol and stomach tissue was obtained after 1 hour. Histological examination was done on hematoxylin and eosin, periodic acid-Schiff, and immunochemically stained gastric mucosal tissues. Prostaglandin E2, superoxide dismutase, catalase, glutathione peroxidase, and lipid peroxidation levels of the gastric tissue homogenates were also determined. Significantly (P<0.05) smaller ulcer areas, less intense edema, and fewer leukocytes’ infiltration were observed in MECE- and omeprazole-treated than in untreated gastric mucosa with ulcer. The gastric pH, mucus production, superoxide dismutase, catalase, and glutathione peroxidase contents increased, while the lipid peroxidation content decreased as a result of MECE treatment. Bcl-2-associated X protein was underexpressed, while heat shock protein 70 and transforming growth factor-beta protein were overexpressed in the ulcerated gastric mucosa tissues treated with omeprazole and MECE. Similarly, there was a reduction in the levels of tumor necrotic factor-alpha and interleukin-6, while the level of interleukin-10 was increased. This study showed that the gastroprotective effect of MECE is achieved through inhibition of gastric juice secretion and ulcer lesion development, stimulation of mucus secretion, elevation of gastric pH, reduction of reactive oxygen species production, inhibition of apoptosis in the gastric mucosa, and modulation of inflammatory cytokines. PMID:27366052

  8. Protective effect of chelerythrine against ethanol-induced gastric ulcer in mice.

    PubMed

    Li, Wei-Feng; Hao, Ding-Jun; Fan, Ting; Huang, Hui-Min; Yao, Huan; Niu, Xiao-Feng

    2014-02-05

    The quaternary benzo[c]phenanthridine alkaloid, chelerythrine (CHE), is of great practical and research interest because of its pronounced, widespread physiological effects, primarily antimicrobial and anti-inflammatory, arising from its ability to interact with proteins and DNA. Although CHE was originally shown to possess anti-inflammatory properties, its effects on acute gastric ulcer have not been previously explored. The aim of the present study is to evaluate the protective effect of CHE on ethanol induced gastric ulcer in mice. Administration of CHE at doses of 1, 5 and 10mg/kg bodyweight prior to ethanol ingestion dose-dependently inhibited gastric ulcer. The gastric mucosal lesion was assessed by ulcer area, gastric juice acidity, myeloperoxidase (MPO) activities, macroscopic and histopathological examinations. CHE significantly reduced the gastric ulcer index, myeloperoxidase activities, macroscopic and histological score in a dose-dependent manner. In addition, CHE also significantly inhibited nitric oxide (NO) concentration, pro-inflammatory interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) level in serum and gastric mucosal in the mice exposed to ethanol induced ulceration in a dose-dependent manner. In addition, immunohistochemical analysis revealed that CHE markedly attenuated the overexpression of nuclear factor-κB in gastric mucosa of mice. It was concluded that CHE represents a potential therapeutic option to reduce the risk of gastric ulceration. In addition, acute toxicity study revealed no abnormal sign to the mice treated with CHE (15mg/kg). These findings suggest that the gastroprotective activity of CHE might contribute in adjusting the inflammatory cytokine by regulating the NF-κB signalling pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. Protective interventions to prevent aflatoxin-induced carcinogenesis in developing countries.

    PubMed

    Groopman, John D; Kensler, Thomas W; Wild, Christopher P

    2008-01-01

    The public health impact of aflatoxin exposure is pervasive in economically developing countries; consequently, we need to design intervention strategies for prevention that are practicable for these high-risk populations. The adverse health consequences of aflatoxins in populations are quite varied, eliciting acute effects, such as rapid death, and chronic outcomes, such as hepatocellular carcinoma. Furthermore, a number of epidemiological studies describe a variety of general adverse health effects associated with aflatoxin, such as impaired growth in children. Thus, the magnitude of the problem is disseminated across the entire spectrum of age, gender, and health status in the population. The aflatoxins multiplicatively increase the risk of liver cancer in people chronically infected with hepatitis B virus (HBV), which illustrates the deleterious impact that even low toxin levels in the diet can pose for human health. Thus other aflatoxin interactions, which likely contribute to the disease burden, still remain to be identified. Therefore, many diverse and appropriate strategies for disease prevention are needed to decrease the incidence of aflatoxin carcinogenesis in developing countries.

  10. Chemopreventive potential of diallylsulfide, lycopene and theaflavin during chemically induced colon carcinogenesis in rat colon through modulation of cyclooxygenase-2 and inducible nitric oxide synthase pathways.

    PubMed

    Sengupta, Archana; Ghosh, Samit; Das, Rajat Kumar; Bhattacharjee, Shamee; Bhattacharya, Sudin

    2006-08-01

    Chemoprevention of colorectal cancer has become essential in the modern industrialized world as cancer of the large bowel has become one of the major causes of cancer mortality, second only to lung cancer. Colon cancer integrates lifestyle factors and multistep genetic alterations, and without preventive intervention, a substantial part of the population is likely to develop colorectal cancer at some point during their lives. Diet and nutrition clearly play a role in the etiology of colon cancer. Inhibitory activity of aqueous suspensions of garlic, tomato and black tea was tested on azoxymethane-induced colon carcinogenesis in Sprague-Dawley rats during earlier studies. In the present study, the protective activity of diallylsulfide and lycopene and theaflavin, important antioxidative ingredients of garlic, tomato and black tea, respectively, was assessed during colon carcinogenesis. The effect was observed on aberrant crypt foci, the preneoplastic lesion. As inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activities is correlated with the prevention of colon cancer, the study continues with the determination of the change in the expression of these proteins. Following treatment, significant reduction in the incidences of aberrant crypt foci (by 43.65% in diallylsulfide, 57.39% in lycopene and 66.08% in theaflavin group) was observed, which was in accordance with the reduced expression of cyclooxygenase-2 and inducible nitric oxide synthase. The effect of the intact source was found to be more pronounced than their components used separately.

  11. Hypoxia-Inducible lncRNA-AK058003 Promotes Gastric Cancer Metastasis by Targeting γ-Synuclein12

    PubMed Central

    Wang, Yafang; Liu, Xiangqiang; Zhang, Hongbo; Sun, Li; Zhou, Yongan; Jin, Haifeng; Zhang, Hongwei; Zhang, Hui; Liu, Jiaming; Guo, Hao; Nie, Yongzhan; Wu, Kaichun; Fan, Daiming; Zhang, Helong; Liu, Lili

    2014-01-01

    Hypoxia has been implicated as a crucial microenvironmental factor that induces cancer metastasis. We previously reported that hypoxia could promote gastric cancer (GC) metastasis, but the underlying mechanisms are not clear. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of carcinogenesis that act on multiple pathways. However, whether lncRNAs are involved in hypoxia-induced GC metastasis remains unknown. In this study, we investigated the differentially expressed lncRNAs resulting from hypoxia-induced GC and normoxia conditions using microarrays and validated our results through real-time quantitative polymerase chain reaction. We found an lncRNA, AK058003, that is upregulated by hypoxia. AK058003 is frequently upregulated in GC samples and promotes GC migration and invasion in vivo and in vitro. Furthermore, AK058003 can mediate the metastasis of hypoxia-induced GC cells. Next, we identified γ-synuclein (SNCG), which is a metastasis-related gene regulated by AK058003. In addition, we found that the expression of SNCG is positively correlated with that of AK058003 in the clinical GC samples used in our study. Furthermore, we found that the SNCG gene CpG island methylation was significantly increased in GC cells depleted of AK058003. Intriguingly, SNCG expression is also increased by hypoxia, and SNCG upregulation by AK058003 mediates hypoxia-induced GC cell metastasis. These results advance our understanding of the role of lncRNA-AK058003 as a regulator of hypoxia signaling, and this newly identified hypoxia/lncRNA-AK058003/SNCG pathway may help in the development of new therapeutics. PMID:25499222

  12. Inhibition of autophagy promotes metastasis and glycolysis by inducing ROS in gastric cancer cells.

    PubMed

    Qin, Wenjie; Li, Chao; Zheng, Wen; Guo, Qingqu; Zhang, Yuefeng; Kang, Muxing; Zhang, Bo; Yang, Bin; Li, Baozhong; Yang, Haijun; Wu, Yulian

    2015-11-24

    Autophagy defect has been shown to be correlated with malignant phenotype and poor prognosis of human cancers, however, the detailed mechanisms remain obscure. In this study, we investigated the biological changes induced by autophagy inhibition in gastric cancer. We showed that inhibition of autophagy in gastric cancer cells promotes epithelial-mesenchymal transition (EMT) and metastasis, alters metabolic phenotype from mitochondrial oxidative phosphorylation to aerobic glycolysis and converts cell phenotype toward malignant, which maybe further contribute to chemoresistance and poor prognosis of gastric cancer. We also identified that the EMT and metabolism alterations induced by autophagy inhibition were dependent on ROS-NF-κB-HIF-1α pathway. More importantly, scavenging of ROS by the antioxidant N-acetylcysteine (NAC) attenuated activation of NF-κB and HIF-1α in autophagy-deficient gastric cancer cells, and autophagy inhibition induced metastasis and glycolysis were also diminished by NAC in vivo. Taken together, our findings suggested that autophagy defect promotes metastasis and glycolysis of gastric cancer, and antioxidants could be used to improve disease outcome for gastric cancer patients with autophagy defect.

  13. Taenia taeniaeformis larval product induces gastric mucosal hyperplasia in SCID mice.

    PubMed

    Lagapa, Jose Trinipil G; Oku, Yuzaburo; Nonaka, Nariaki; Kamiya, Masao

    2002-02-01

    The effects of intraperitoneal implantation of Taenia taeniaeformis larvae and inoculation of in vitro larval products on gastric mucosa of SCID mice were investigated in this study. Mice surgically implanted with T. taeniaeformis larvae developed slight and moderate gastric hyperplasia. When in vitro cultured T. taeniaeformis larval excretory-secretory (TtLES) products containing 1 mg of protein were injected daily into mice, they caused gastropathy after 5-7 days. Mice injected daily with 0.5 mg of TtLES products also showed slight gastric hyperplasia after day 14 and 28. The gastropathy was characterized by reduction of both parietal and zymogenic cell number and increased number of alcian blue-periodic acid Schiff (AB-PAS)-positive cells and by two-fold extension of proliferative zone of gastric units. Larval implantation demonstrated a more potent effect in inducing gastropathy than did in vitro larval culture products. Significant decrease in number of parietal cells with concomitant increase of proliferative zone and AB-PAS-positive cell number indicated their important roles in inducing the hyperplastic lesion. Similarities with other gastropathies indicated that there is a common fundamental regulatory mechanism involved, and that the host response may not be specific to parasites. Present study validated the induction of gastric mucosal hyperplasia by larval ES products of T. taeniaeformis. This proved the hypothesis of previous studies suggesting the role of larvae-derived products in inducing gastric mucosal hyperplasia in T. taeniaeformis-infected rats.

  14. Antibiotic drug tigecycline inhibited cell proliferation and induced autophagy in gastric cancer cells

    SciTech Connect

    Tang, Chunling; Yang, Liqun; Jiang, Xiaolan; Xu, Chuan; Wang, Mei; Wang, Qinrui; Zhou, Zhansong; Xiang, Zhonghuai; Cui, Hongjuan

    2014-03-28

    Highlights: • Tigecycline inhibited cell growth and proliferation in human gastric cancer cells. • Tigecycline induced autophagy not apoptosis in human gastric cancer cells. • AMPK/mTOR/p70S6K pathway was activated after tigecycline treatment. • Tigecycline inhibited tumor growth in xenograft model of human gastric cancer cells. - Abstract: Tigecycline acts as a glycylcycline class bacteriostatic agent, and actively resists a series of bacteria, specifically drug fast bacteria. However, accumulating evidence showed that tetracycline and their derivatives such as doxycycline and minocycline have anti-cancer properties, which are out of their broader antimicrobial activity. We found that tigecycline dramatically inhibited gastric cancer cell proliferation and provided an evidence that tigecycline induced autophagy but not apoptosis in human gastric cancer cells. Further experiments demonstrated that AMPK pathway was activated accompanied with the suppression of its downstream targets including mTOR and p70S6K, and ultimately induced cell autophagy and inhibited cell growth. So our data suggested that tigecycline might act as a candidate agent for pre-clinical evaluation in treatment of patients suffering from gastric cancer.

  15. EF24 induces ROS-mediated apoptosis via targeting thioredoxin reductase 1 in gastric cancer cells

    PubMed Central

    Chen, Weiqian; Chen, Xi; Ying, Shilong; Feng, Zhiguo; Chen, Tongke; Ye, Qingqing; Wang, Zhe; Qiu, Chenyu; Yang, Shulin; Liang, Guang

    2016-01-01

    Gastric cancer (GC) is one of the leading causes of cancer mortality in the world, and finding novel agents for the treatment of advanced gastric cancer is of urgent need. Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, exhibits potent anti-tumor activities by arresting cell cycle and inducing apoptosis. Although EF24 demonstrates potent anticancer efficacy in numerous types of human cancer cells, the cellular targets of EF24 have not been fully defined. We report here that EF24 may interact with the thioredoxin reductase 1 (TrxR1), an important selenocysteine (Sec)-containing antioxidant enzyme, to induce reactive oxygen species (ROS)-mediated apoptosis in human gastric cancer cells. By inhibiting TrxR1 activity and increasing intracellular ROS levels, EF24 induces a lethal endoplasmic reticulum stress in human gastric cancer cells. Importantly, knockdown of TrxR1 sensitizes cells to EF24 treatment. In vivo, EF24 treatment markedly reduces the TrxR1 activity and tumor cell burden, and displays synergistic lethality with 5-FU against gastric cancer cells. Targeting TrxR1 with EF24 thus discloses a previously unrecognized mechanism underlying the biological activity of EF24, and reveals that TrxR1 is a good target for gastric cancer therapy. PMID:26919110

  16. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and {beta}-adrenergic receptor signaling pathways

    SciTech Connect

    Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K.; Cho, C.H.; Sung, J.J.Y.

    2008-12-01

    Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor ({alpha}7 nAChR) and {beta}-adrenergic receptors. Treatment of cells with {alpha}-bungarotoxin ({alpha}-BTX, {alpha}7nAChR antagonist) or propranolol ({beta}-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE{sub 2} and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE{sub 2} induction can only be suppressed by propranolol, but not {alpha}-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis.

  17. IL-22 Negatively Regulates Helicobacter pylori-Induced CCL20 Expression in Gastric Epithelial Cells

    PubMed Central

    Chen, Jia-Perng; Wu, Ming-Shiang; Kuo, Sung-Hsin; Liao, Fang

    2014-01-01

    Helicobacter pylori is a Gram-negative bacterium that infects the human gastric mucosa and causes various gastric diseases. H. pylori infection induces the production of inflammatory chemokine CCL20 in gastric mucosa and leads to gastric inflammation. Given that the IL-22/IL-22R axis plays a critical role in the regulation of homeostasis and inflammation of epithelial cells at barrier surfaces, we investigated the effect of IL-22 on CCL20 expression induced by H. pylori. We demonstrated that H. pylori infection of the gastric epithelia-derived AGS cells significantly induced CCL20 expression and the induction was inhibited by IL-22. Functional analysis of the CCL20 promoter revealed that the H. pylori-induced CCL20 expression required the activation of NF-κB, and that IL-22 inhibited the induction by attenuating NF-κB activation. Knockdown of endogenous STAT3 by either short interfering RNAs or a short hairpin RNA significantly reduced the inhibitory effect of IL-22. Furthermore, STAT3 phosphorylation elicited by IL-22 was crucial for the inhibition of H. pylori-induced CCL20 expression. Consistent with the in vitro data showing that IL-22 negatively regulated H. pylori-induced CCL20 expression in gastric epithelial cells, studies on the tissue sections from patients with H. pylori infection also revealed an inverse association of IL-22 expression and CCL20 expression in vivo. Together, our findings suggest that IL-22 plays a role in the control of overproduction of the inflammatory chemokine and thus may protect the gastric mucosa from inflammation-mediated damage. PMID:24824519

  18. Use of Transgenic and Mutant Animal Models in the Study of Heterocyclic Amine-induced Mutagenesis and Carcinogenesis

    PubMed Central

    Dashwood, Roderick H.

    2008-01-01

    Heterocyclic amines (HCAs) are potent mutagens generated during the cooking of meat and fish, and several of these compounds produce tumors in conventional experimental animals. During the past 5 years or so, HCAs have been tested in a number of novel in vivo murine models, including the following: lacZ, lacI, cII, c-myc/lacZ, rpsL, and gptΔ transgenics, XPA−/−, XPC−/−, Msh2+/−, Msh2−/− and p53+/− knock-outs, Apc mutant mice (ApcΔ716, Apc1638N, Apcmin), and A33ΔNβ-cat knock-in mice. Several of these models have provided insights into the mutation spectra induced in vivo by HCAs in target and non-target organs for tumorigenesis, as well as demonstrating enhanced susceptibility to HCA-induced tumors and preneoplastic lesions. This review describes several of the more recent reports in which novel animal models were used to examine HCA-induced mutagenesis and carcinogenesis in vivo, including a number of studies which assessed the inhibitory activities of chemopreventive agents such as 1,2-dithiole-3-thione, conjugated linoleic acids, tea, curcumin, chlorophyllin-chitosan, and sulindac. PMID:12542973

  19. Inhibitory effects of chlorophyllin on 7,12-dimethylbenz[a]anthracene-induced bacterial mutagenesis and mouse skin carcinogenesis.

    PubMed

    Chung, W Y; Lee, J M; Park, M Y; Yook, J I; Kim, J; Chung, A S; Surh, Y J; Park, K K

    1999-10-18

    Chlorophyllin (CHL), a water-soluble derivative of chlorophyll, has been used for the treatment of several abnormal human conditions without apparent toxicity. Recent studies have revealed that CHL has the excellent chemopreventive potential. In the present investigation, we have found the inhibitory activities of CHL against 7,12-dimethylbenz[a]anthracene (DMBA)-induced mutagenesis in Salmonella typhimurium TA100 and also on DMBA-initiated and 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-promoted mouse skin tumor formation. The incidence and the multiplicity of skin tumors were not significantly decreased in mice by a single topical application of CHL prior to the DMBA treatment, but there was a marked suppression of papillomagenesis in mice treated with CHL during the promotional stage. Furthermore, the formation of DMBA-induced papillomagenesis was reduced in all mice that had received CHL for 6 weeks following treatment with TPA for 6, 18 and 24 weeks. These results indicate that CHL can inhibit both tumor promotion and the progression of papillomagenesis in the two-stage mouse skin carcinogenesis induced by DMBA and TPA.

  20. KLF4 deletion alters gastric cell lineage and induces MUC2 expression

    PubMed Central

    Yu, T; Chen, X; Lin, T; Liu, J; Li, M; Zhang, W; Xu, X; Zhao, W; Liu, M; Napier, D L; Wang, C; Evers, B M; Liu, C

    2016-01-01

    Gastric cancer is one of the most common types of cancer in the world, particularly in underdeveloped countries. The mechanism of gastric cancer is less understood compared with other types of gastrointestinal (GI) cancers. Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor and is a potential tumor suppressor in GI cancers. In this study, we have generated two mouse models, Rosa-Cre;Klf4fl/fl and Lgr5-Cre;Klf4fl/fl. KLF4 was deleted by Rosa-Cre in the gastric epithelia cells or by Lgr5-Cre in the antral stem cells in the adult mice. KLF4 deletion resulted in increased proliferating cells and decreased pit mucous cells. Surprisingly, the intestinal goblet cell marker, MUC2, which is not expressed in normal gastric tissues, was strongly induced at the base of the KLF4-deleted antral glands. To understand the clinical relevance of these findings, we analyzed the expression of KLF4 and MUC2 in human gastric cancer. In a subset of human gastric cancer, the expression of KLF4 is negatively associated with MUC2 expression. In conclusion, KLF4 is essential for normal homeostasis of antral stem cells; loss of KLF4 and expression of MUC2 could be important markers for gastric cancer diagnosis. PMID:27277677

  1. Magnesium sulfate induced toxicity in vitro in AGS gastric adenocarcinoma cells and in vivo in mouse gastric mucosa.

    PubMed

    Zhang, Xulong; Bo, Agula; Chi, Baofeng; Xia, Yuan; Su, Xiong; Sun, Juan

    2015-01-01

    Magnesium sulfate is widely used as a food additive and as an orally administered medication. The aim of this study was to evaluate the possible cytotoxicity of magnesium sulfate on AGS human gastric adenocarcinoma cells and gastric mucosa in mice. A trypan blue exclusion assay was used to determine the reduction in viability of AGS cells exposed to magnesium sulfate, and then effects on cell proliferation were quantified. The role of magnesium sulfate-mediated pro-inflammatory cytokine production in AGS cells was also investigated. mRNA expression for IL-1β, IL-6, IL-8, and TNF-α was determined by RT-PCR, and secretion of these cytokines was measured by ELISA. Immunohistochemical evaluation of IL-1β, IL-6, and TNF-α expression was conducted in mouse gastric mucosa. Addition of 3 to 50 mM magnesium sulfate to AGS cells inhibited both cell proliferation and cell viability in a dose-dependent manner. Magnesium sulfate had little effect on production of IL-1β or IL-6 but significantly inhibited production of IL-8. The animal model demonstrated that magnesium sulfate induced production of IL-1β, IL-6, and TNF-α. These preliminary data suggest that magnesium sulfate had a direct effect on the stomach and initiates cytotoxicity in moderate concentrations and time periods by inhibiting viability and proliferation of AGS cells and by regulating expression and/or release of pro-inflammatory cytokines.

  2. Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis.

    PubMed

    Lertpiriyapong, Kvin; Whary, Mark T; Muthupalani, Sureshkumar; Lofgren, Jennifer L; Gamazon, Eric R; Feng, Yan; Ge, Zhongming; Wang, Timothy C; Fox, James G

    2014-01-01

    Gastric colonisation with intestinal flora (IF) has been shown to promote Helicobacter pylori (Hp)-associated gastric cancer. However, it is unknown if the mechanism involves colonisation with specific or diverse microbiota secondary to gastric atrophy. Gastric colonisation with Altered Schaedler's flora (ASF) and Hp were correlated with pathology, immune responses and mRNA expression for proinflammatory and cancer-related genes in germ-free (GF), Hp monoassociated (mHp), restricted ASF (rASF; 3 species), and specific pathogen-free (complex IF), hypergastrinemic INS-GAS mice 7 months postinfection. Male mice cocolonised with rASFHp or IFHp developed the most severe pathology. IFHp males had the highest inflammatory responses, and 40% developed invasive gastrointestinal intraepithelial neoplasia (GIN). Notably, rASFHp colonisation was highest in males and 23% developed invasive GIN with elevated expression of inflammatory biomarkers. Lesions were less severe in females and none developed GIN. Gastritis in male rASFHp mice was accompanied by decreased Clostridum species ASF356 and Bacteroides species ASF519 colonisation and an overgrowth of Lactobacillus murinus ASF361, supporting that inflammation-driven atrophy alters the gastric niche for GI commensals. Hp colonisation also elevated expression of IL-11 and cancer-related genes, Ptger4 and Tgf-β, further supporting that Hp infection accelerates gastric cancer development in INS-GAS mice. rASFHp colonisation was sufficient for GIN development in males, and lower GIN incidence in females was associated with lower inflammatory responses and gastric commensal and Hp colonisation. Colonisation efficiency of commensals appears more important than microbial diversity and lessens the probability that specific gastrointestinal pathogens are contributing to cancer risk.

  3. Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis

    PubMed Central

    Lertpiriyapong, Kvin; Whary, Mark T.; Muthupalani, Sureshkumar; Lofgren, Jennifer L.; Gamazon, Eric R.; Feng, Yan; Ge, Zhongming; Wang, Timothy C.; Fox, James G.

    2014-01-01

    Objectives Gastric colonisation with intestinal flora (IF) has been shown to promote Helicobacter pylori (Hp)-associated gastric cancer. However, it is unknown if the mechanism involves colonisation with specific or diverse microbiota secondary to gastric atrophy. Design Gastric colonisation with Altered Schaedler’s flora (ASF) and Hp were correlated with pathology, immune responses and mRNA expression for proinflammatory and cancer-related genes in germ-free (GF), Hp monoassociated (mHp), restricted ASF (rASF; 3 species), and specific pathogen-free (complex IF), hypergastrinemic INS-GAS mice 7 months postinfection. Results Male mice cocolonised with rASFHp or IFHp developed the most severe pathology. IFHp males had the highest inflammatory responses, and 40% developed invasive gastrointestinal intraepithelial neoplasia (GIN). Notably, rASFHp colonisation was highest in males and 23% developed invasive GIN with elevated expression of inflammatory biomarkers. Lesions were less severe in females and none developed GIN. Gastritis in male rASFHp mice was accompanied by decreased Clostridum species ASF356 and Bacteroides species ASF519 colonisation and an overgrowth of Lactobacillus murinus ASF361, supporting that inflammation-driven atrophy alters the gastric niche for GI commensals. Hp colonisation also elevated expression of IL-11 and cancer-related genes, Ptger4 and Tgf-β, further supporting that Hp infection accelerates gastric cancer development in INS-GAS mice. Conclusions rASFHp colonisation was sufficient for GIN development in males, and lower GIN incidence in females was associated with lower inflammatory responses and gastric commensal and Hp colonisation. Colonisation efficiency of commensals appears more important than microbial diversity and lessens the probability that specific gastrointestinal pathogens are contributing to cancer risk. PMID:23812323

  4. Sulindac sulfide induces autophagic death in gastric epithelial cells via survivin down-regulation: a mechanism of NSAIDs-induced gastric injury.

    PubMed

    Chiou, Shiun-Kwei; Hoa, Neil; Hodges, Amy

    2011-06-01

    Sulindac sulfide, a nonsteroidal anti-inflammatory drug (NSAID), has anti-tumorigenic and anti-inflammatory activities, but causes gastric mucosal damage. NSAIDs cause gastric injury in part by down-regulation of Survivin, an apoptosis inhibitor, resulting in apoptosis induction. Autophagy is a process that promotes cellular health by destroying unwanted cellular materials. Excessive autophagy induction could lead to a non-apoptotic cell death (autophagic cell death). The present study showed that sulindac sulfide at a physiological concentration also induces autophagic death in human gastric epithelial AGS and rat gastric epithelial RGM-1 cells, and that Survivin down-regulation is a mechanism involved: Sulindac sulfide treatment increased LC3b-II and APG7 levels and cytosolic vacuole formation, indications of autophagy induction, in AGS and RGM-1 cells. Sulindac sulfide treatment induced AGS and RGM-1 cell death, which was significantly reduced by pretreatment with the autophagy inhibitors 3-methyladenine and chloroquine, indicating that sulindac sulfide induced autophagic cell death. Stable overexpression of Survivin in RGM-1 cells did not inhibit the induction of LC3b-II levels or vacuole formation by sulindac sulfide, but significantly reduced the resulting cell death, suggesting that Survivin may inhibit autophagic cell death downstream of LC3b-II induction and vacuole formation. Indeed, siRNA depletion of LC3b in AGS cells inhibited the down-regulation of Survivin levels and the induction of cell death by sulindac sulfide, confirming that down-regulation of Survivin occurs in the autophagy pathway downstream of LC3b-II induction by sulindac sulfide. Induction of Survivin-dependent autophagic cell death is a novel mechanism by which sulindac sulfide induces gastric mucosal injury. Published by Elsevier Inc.

  5. Recent progress in carcinogenesis, progression and management of upper GI cancer: the 21st Hiroshima Cancer Seminar--the 5th Three Universities' Consortium International Symposium, 6 November 2011, International Conference Center Hiroshima.

    PubMed

    Yasui, Wataru; Ito, Hisao; Peek, Richard; Tahara, Eiichi

    2012-04-01

    The 21st Hiroshima Cancer Seminar focused on recent progress of carcinogenesis, progression and management of upper gastrointestinal cancers. β-Catenin and p120 mediate peroxisome proliferator-activated receptor δ-dependent proliferation induced by Helicobacter pylori in gastric epithelia. Helicobacter pylori CagA plays an important role in stomach carcinogenesis via altered signal transduction and cell polarity by interactions with several host proteins. Inflammation caused by H. pylori infection is responsible for inducing aberrant DNA methylation. The gastric gland mucin-specific αGlcNAc plays dual roles in preventing gastric cancer, inhibition of H. pylori infection and suppression of tumor-promoting inflammation. Information obtained from transcriptome dissection greatly contributes to understanding the molecular character of each mucin phenotype of gastric cancer. The standardized biomarkers will serve as good predictive and prognostic markers for gastric cancer. A microRNA expression profile may be useful for the diagnosis of gastric cancer. Bone marrow-derived mesenchymal stem cells may provide an advantageous microenvironment for re-acquisition of stemness of gastric cancer cells. Recent progress in molecular biology research has enabled the clinical development of molecular targeting agents for gastric cancer, such as trastuzumab. The target molecule-based inhibition of the stromal reaction in the microenvironment may hold promise as an effective anti-tumor therapy. Since robotic surgery is feasible and safe, and provides adequate and precise lymph node dissection, it may be one of the good options for gastric cancer in the near future.

  6. Polymeric black tea polyphenols inhibit 1,2-dimethylhydrazine induced colorectal carcinogenesis by inhibiting cell proliferation via Wnt/{beta}-catenin pathway

    SciTech Connect

    Patel, Rachana; Ingle, Arvind; Maru, Girish B.

    2008-02-15

    Tea polyphenols like epigallocatechin gallate and theaflavins are established chemopreventive agents for colorectal carcinogenesis. However, studies on evaluating similar chemopreventive properties of thearubigins or polymeric black tea polyphenols (PBPs), the most abundant polyphenols in black tea, are limited. Hence, in the present study we aim to investigate chemopreventive effects along with probable mechanisms of action of PBP extract employing 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis in Sprague-Dawley rats as experimental model. The present study suggests that PBPs, like other tea polyphenols, also inhibit DMH-induced colorectal tumorigenesis by decreasing tumor volume and multiplicity. This study also shows that although the pretreatment with PBP extract could induce detoxifying enzymes in hepatic and colorectal tissue, it did not show any additional chemopreventive effects when compared to treatments with PBP extract after initiation with DMH. Mechanistically, PBP extract may inhibit colorectal carcinogenesis by decreasing DMH-induced cell proliferation via Wnt/{beta}-catenin pathway. Treatments with PBP extract showed decreased levels of COX-2, c-MYC and cyclin D1 proteins which aid cell proliferation probably by regulating {beta}-catenin by maintaining expression of APC and decreasing inactivation of GSK3{beta}. DMH-induced activation of MAP kinases such as ERK and JNK was also found to be inhibited by treatments with PBP extract. In conclusion, the protective effects of PBP extract could be attributed to inhibition of DMH-induced cellular proliferation probably through {beta}-catenin regulation.

  7. Intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

    PubMed Central

    Choudhary, Shambhunath; Sood, Shilpa; Donnell, Robert L.; Wang, Hwa-Chain R.

    2012-01-01

    More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental carcinogens, such as those in the diet, through a multistep disease process progressing from non-cancerous to premalignant and malignant stages. The chemical carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the most abundant heterocyclic amines found in high-temperature cooked meats and is recognized as a mammary carcinogen. However, the PhIP’s mechanism of action in breast cell carcinogenesis is not clear. Here, we demonstrated, for the first time, that cumulative exposures to PhIP at physiologically achievable, pico to nanomolar concentrations effectively induced progressive carcinogenesis of human breast epithelial MCF10A cells from a non-cancerous stage to premalignant and malignant stages in a dose- and exposure-dependent manner. Progressive carcinogenesis was measured by increasingly- acquired cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, acinar-conformational disruption, proliferation, migration, invasion, tumorigenicity with metastasis and increased stem-like cell populations. These biological changes were accompanied by biochemical and molecular changes, including upregulated H-Ras gene expression, extracellular signal-regulated kinase (ERK) pathway activation, Nox-1 expression, reactive oxygen species (ROS) elevation, increased HIF-1α, Sp1, tumor necrosis factor-α, matrix metalloproteinase (MMP)-2, MMP-9, aldehyde dehydrogenase activity and reduced E-cadherin. The Ras-ERK-Nox-ROS pathway played an important role in not only initiation but also maintenance of cellular carcinogenesis induced by PhIP. Using biological, biochemical and molecular changes as targeted endpoints, we identified that the green tea catechin components epicatechin-3-gallate and epigallocatechin-3-gallate, at non-cytotoxic doses, were capable of suppressing PhIP-induced cellular carcinogenesis and

  8. Mechanism of selenium-induced inhibition of arsenic-enhanced UVR carcinogenesis in mice.

    PubMed

    Burns, Fredric J; Rossman, Toby; Vega, Katherine; Uddin, Ahmed; Vogt, Stefan; Lai, Barry; Reeder, Richard J

    2008-06-01

    Hairless mice that ingested arsenite in drinking water exhibited more than a 5-fold enhancement of ultraviolet radiation (UVR) carcinogenesis, whereas arsenite alone was carcinogenically inactive. Dietary organoselenium blocked the cancer enhancement effect of arsenic but not cancer induction by UVR. In this study we sought to explain selenium blockage of As enhancement by establishing the extent that As and Se tissue distributions are coincident or divergent. We used the X-ray fluorescence microprobe at the Advanced Photon Source (Argonne National Laboratory) to probe sections of skin and liver from hairless mice exposed to a) UVR, b) UVR + As, c) UVR + organoselenium, or d) UVR + As + organoselenium. We found elevated levels of As in the skin epithelium (hair follicles and epidermis) and diffusely in the liver of mice exposed to UVR + As. Arsenic was entirely absent in skin in mice exposed to UVR + As + organoselenium, but a diffuse low level was seen in the liver. As and Se locations were consistently divergent in skin; As was more diffusely distributed, whereas Se was strongly associated with membranes. X-ray absorption near-edge spectra are consistent with the presence of the seleno-bis(S-glutathionyl) arsinium ion in the liver. Supplemental Se was uncommonly effective at preventing even a trace of As in skin at 14 or 196 days of continuous exposure to As in drinking water. Traces of the seleno-bis(S-glutathionyl) arsinium ion in the liver suggested that formation of this compound was more likely to be responsible for the As-blocking effect of Se than was a mechanism based on antioxidation.

  9. High susceptibility to azoxymethane-induced colorectal carcinogenesis in obese KK-Ay mice.

    PubMed

    Teraoka, Naoya; Mutoh, Michihiro; Takasu, Shinji; Ueno, Toshiya; Nakano, Katsuya; Takahashi, Mami; Imai, Toshio; Masuda, Shuichi; Sugimura, Takashi; Wakabayashi, Keiji

    2011-08-01

    Obesity is associated with colon carcinogenesis. However, not much information is available regarding the mechanisms of obesity-associated colorectal cancer, and there are only few useful animal models for investigating the underlying mechanism between obesity and colorectal cancer. KK-A(y) mice exhibit severe obesity. Amount of visceral fat assessed by micro-computed tomography was almost 15 times higher than that of same aged C57BL/6J mice. Treatment with azoxymethane (AOM; 200 μg/mouse injected once a week for 3 times) resulted in markedly increased colon aberrant crypt foci (ACF) development (≈70 ACF/mouse) in KK-A(y) mice compared with lean C57BL/6J mice (≈9 ACF/mouse). Moreover, administration of AOM at a dose of 200 μg/mouse once a week for 6 times developed colorectal adenocarcinomas within only 7 weeks after the last AOM injection. The incidence of adenocarcinoma was 88% in KK-A(y) mice and was markedly higher than the 4% observed in C57BL/6J mice. The number of tumors/mouse was 7.80 in KK-A(y) mice and also markedly higher than the 0.12 in the C57BL/6J case. Interestingly, adenocarcinomas were observed in most of the AOM-treated KK-A(y) mice along with remarkable tumor angiogenesis, and some showed submucosal invasion. These results indicate that the KK-A(y) mouse, featuring intact leptin and leptin receptor Ob-Rbl, could be a useful animal model to investigate obesity-associated cancer. Copyright © 2010 UICC.

  10. Intrahepatic polyamine levels during rat liver carcinogenesis induced by N-2-fluorenylacetamide.

    PubMed

    Milano, G; Aussel, C; Stora, C; Lafaurie, M; Soula, G; Lalanne, C M

    1981-01-01

    During a period of 200 days, the chronological changes of polyamine levels (putrescine, spermidine and spermine) were observed in the liver of adult female Sprague Dawley rats submitted to hepatocarcinogenesis by N-2-fluorenylacetamide (FAA). Three groups of 70 rats each were used: (1) Control 1: normal diet; (2) Control 2: low protein and low riboflavin diet; and (3) EXPERIMENTAL: 0.06% FAA added to the diet. No significant differences were noted for tissue levels of the three polyamines when the two control groups were compared. In contrast, considerable variations of these molecules were observed as a function of time in the FAA treated group: (a) an early and constant rise was seen in putrescine, with 3 maxima at days 10, 60 and 150. This last peak was the highest: 25 +/- 6 nmol/g (8 times the value for the controls at this time), and coincided with the appearance of cancerous lesions. (b) While spermidine levels varied during the experiment, no significant differences were noted in comparison with the control groups. Mean levels (nmol/g) were: 535 +/- 108 Control 1; 552 +/- 95 Control 2; 633 +/- 160 FAA-treated group. (c) Spermine levels were significantly lowered, with 3 minima corresponding to the putrescine maxima. The lowest minima was observed on day 60: 114 +/- 67 nmol/g, i.e., 4 times lower than the controls. This work shows that polyamine metabolism is profoundly modified during chemical carcinogenesis, but the possible effect of polyamines on tumorigenesis itself cannot be assessed at this point since modifications of polyamine levels are probably also associated with phenomena of liver necrosis and compensatory tissue proliferation observed during the experiment.

  11. Mechanism of Selenium-Induced Inhibition of Arsenic-Enhanced UVR Carcinogenesis in Mice

    PubMed Central

    Burns, Fredric J.; Rossman, Toby; Vega, Katherine; Uddin, Ahmed; Vogt, Stefan; Lai, Barry; Reeder, Richard J.

    2008-01-01

    Background Hairless mice that ingested arsenite in drinking water exhibited more than a 5-fold enhancement of ultraviolet radiation (UVR) carcinogenesis, whereas arsenite alone was carcinogenically inactive. Dietary organoselenium blocked the cancer enhancement effect of arsenic but not cancer induction by UVR. Objective In this study we sought to explain selenium blockage of As enhancement by establishing the extent that As and Se tissue distributions are coincident or divergent. Methods We used the X-ray fluorescence microprobe at the Advanced Photon Source (Argonne National Laboratory) to probe sections of skin and liver from hairless mice exposed to a) UVR, b) UVR + As, c) UVR + organoselenium, or d) UVR + As + organoselenium. Results We found elevated levels of As in the skin epithelium (hair follicles and epidermis) and diffusely in the liver of mice exposed to UVR + As. Arsenic was entirely absent in skin in mice exposed to UVR + As + organoselenium, but a diffuse low level was seen in the liver. As and Se locations were consistently divergent in skin; As was more diffusely distributed, whereas Se was strongly associated with membranes. X-ray absorption near-edge spectra are consistent with the presence of the seleno-bis(S-glutathionyl) arsinium ion in the liver. Conclusions Supplemental Se was uncommonly effective at preventing even a trace of As in skin at 14 or 196 days of continuous exposure to As in drinking water. Traces of the seleno-bis(S-glutathionyl) arsinium ion in the liver suggested that formation of this compound was more likely to be responsible for the As-blocking effect of Se than was a mechanism based on antioxidation. PMID:18560523

  12. Gastric vascular and motor responses to anaphylactic hypotension in anesthetized rats, in comparison to those with hemorrhagic or vasodilator-induced hypotension.

    PubMed

    Kuda, Yuhichi; Shibamoto, Toshishige; Zhang, Tao; Yang, Wei; Tanida, Mamoru; Kurata, Yasutaka

    2017-01-31

    Anaphylactic shock is life-threatening, but pathophysiology of the stomach lesion remains unclear. We determined gastric hemodynamics and gastric functions during anaphylactic hypotension, as compared to hypotension induced by hemorrhage or sodium nitroprusside (SNP) in anesthetized and ovalbumin-sensitized Sprague-Dawley rats. Systemic arterial pressure, portal venous pressure, and gastric arterial blood flow were measured, and gastric vascular resistance (GVR) was determined. Separately, the intragastric pressure (IGP) and gastric effluent, as a measure of gastric flux, were continuously measured. During anaphylaxis, GVR decreased only transiently at 0.5 min, followed by an increase. IGP increased markedly, while gastric flux decreased. During hemorrhage, GVR and IGP increased, while gastric flux did not change. When SNP was injected, both GVR and IGP decreased and gastric flux increased only just after injection. In conclusion, gastric vasodilatation occurs only transiently after antigen injection, and gastric motility increases, but gastric emptying deceases during anaphylactic hypotension in anesthetized rats.

  13. Attenuation of stress-induced gastric lesions by lansoprazole, PD-136450 and ranitidine in rats.

    PubMed

    Chandranath, S I; Bastaki, S M A; D'Souza, A; Adem, A; Singh, J

    2011-03-01

    Combining restraint with cold temperature (4°C) consistently induces gastric ulceration in rats after 3.5 h. The cold restraint-stress (CRS) method provides a suitable model for acute ulcer investigations. This study compares the antiulcer activities of lansoprazole (a proton pump inhibitor), PD-136450 (CCK(2)/gastrin receptor antagonist) and ranitidine (histamine H(2) receptor antagonist) on CRS-induced gastric ulcers in rats. The results have shown that lansoprazole, which is a potent anti-secretory agent, provides complete protection in this model of ulcer formation. The use of indomethacin pretreatment to inhibit the prostaglandin (PG) synthesis and N(G)-nitro L-arginine methyl ester (L-NAME) pretreatment to inhibit nitric oxide synthase did not alter the lansoprazole-induced inhibition of ulcer index obtained in the untreated Wistar rats indicating that these two systems were not involved in the activation of lansoprazole. PD-136450, an effective anti-secretory agent against gastrin- but not dimaprit-induced stimulation, evoked a dose-dependent inhibition of CRS-induced gastric ulcers. The results show that both PG and nitric oxide pathways can influence the inhibitory effect of PD-136450 against CRS-induced gastric ulcer. The antiulcer activities of both lansoprazole and PD-136450 were compared to that of ranitidine. The results showed that ranitidine was more potent than lansoprazole and PD-136450 in inhibiting CRS-induced gastric ulcers and its effect was shown to be influenced by PG as well as nitric oxide synthase. The results of this study have demonstrated that although lansoprazole, PD-136450 and ranitidine were protective against CRS-induced gastric ulcers, the antiulcer activities of PD-136450 and ranitidine involved both PG and nitric oxide pathways, while lansoprazole acted independently of these two systems during CRS.

  14. Protective role of hydrogen-rich water on aspirin-induced gastric mucosal damage in rats

    PubMed Central

    Zhang, Jing-Yao; Wu, Qi-Fei; Wan, Yong; Song, Si-Dong; Xu, Jia; Xu, Xin-Sen; Chang, Hu-Lin; Tai, Ming-Hui; Dong, Ya-Feng; Liu, Chang

    2014-01-01

    AIM: To investigate the role of the hydrogen-rich water (HRW) in the prevention of aspirin-induced gastric mucosal injury in rats. METHODS: Forty male rats were allocated into four groups: normal control group, HRW group, aspirin group, and HRW plus aspirin group. The protective efficacy was tested by determining the gastric mucosal damage score. Malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), interleukin (IL)-06 and tumor necrosis factor (TNF)-α in gastric tissues were evaluated. The serum levels of IL-1β and TNF-α were also detected. Histopathology of gastric tissues and localization of Cyclooxygenase 2 (COX-2) were detected using hematoxylin and eosin staining and immunohistochemistry, respectively. RESULTS: Pretreatment with HRW obviously reduced aspirin-induced gastric damage scores (4.04 ± 0.492 vs 2.10 ± 0.437, P < 0.05). The oxidative stress levels of MDA and MPO in the gastric tissues increased significantly in the aspirin-treated group compared with the HRW group (2.43 ± 0.145 vs 1.79 ± 0.116 nmol/mg prot, P < 0.05 and 2.53 ± 0.238 vs 1.40 ± 0.208 U/g tissue, P < 0.05, respectively). HRW could obviously elevated the SOD levels in the gastric tissues (37.94 ± 8.44 vs 59.55 ± 9.02 nmol/mg prot, P < 0.05). Pretreatment with HRW significantly reduced IL-06 and TNF-α in the gastric tissues (46.65 ± 5.50 vs 32.15 ± 4.83 pg/mg, P < 0.05 and 1305.08 ± 101.23 vs 855.96 ± 93.22 pg/mg, P < 0.05), and IL-1β and TNF-α in the serum (505.38 ± 32.97 vs 343.37 ± 25.09 pg/mL, P < 0.05 and 264.53 ± 28.63 vs 114.96 ± 21.79 pg/mL, P < 0.05) compared to treatment with aspirin alone. HRW could significantly decrease the COX-2 expression in the gastric tissues (staining score: 8.4 ± 2.1 vs 2.9 ± 1.5, P < 0.05). CONCLUSION: HRW pretreatment alleviated the aspirin-induced gastric lesions by inhibiting the oxidative stress, inflammatory reaction and reducing the COX-2 in the gastric tissues. PMID:24587639

  15. Dehydroabietic Acid Derivative QC4 Induces Gastric Cancer Cell Death via Oncosis and Apoptosis

    PubMed Central

    Luo, Dongjun; Ni, Qing; Ji, Anlai; Gu, Wen; Wu, Junhua

    2016-01-01

    Aim. QC4 is the derivative of rosin's main components dehydroabietic acid (DHA). We investigated the cytotoxic effect of QC4 on gastric cancer cells and revealed the mechanisms beneath the induction of cell death. Methods. The cytotoxic effect of QC4 on gastric cancer cells was evaluated by CCK-8 assay and flow cytometry. The underlying mechanisms were tested by administration of cell death related inhibitors and detection of apoptotic and oncosis related proteins. Cytomembrane integrity and organelles damage were confirmed by lactate dehydrogenase (LDH) leakage assay, mitochondrial function test, and cytosolic free Ca2+ concentration detection. Results. QC4 inhibited cell proliferation dose- and time-dependently and destroyed cell membrane integrity, activated calpain-1 autolysis, and induced apoptotic protein cleavage in gastric cancer cells. The detection of decreased ATP and mitochondrial membrane potential, ROS accumulation, and cytosolic free Ca2+ elevation confirmed organelles damage in QC4-treated gastric cancer cells. Conclusions. DHA derivative QC4 induced the damage of cytomembrane and organelles which finally lead to oncosis and apoptosis in gastric cancer cells. Therefore, as a derivative of plant derived small molecule DHA, QC4 might become a promising agent in gastric cancer therapy. PMID:27057539

  16. Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat.

    PubMed

    Miyoshi, Mami; Kasahara, Emiko; Park, Ah-Mee; Hiramoto, Keiichi; Minamiyama, Yukiko; Takemura, Shigekazu; Sato, Eisuke F; Inoue, Masayasu

    2003-01-01

    Dietary nitrate is reduced to nitrite by some oral bacteria and the resulting nitrite is converted to nitric oxide (NO) in acidic gastric juice. The aim of this study is to elucidate the pathophysiological role of dietary nitrate in the stomach. Intragastric administration of nitrate rapidly increased nitrate and NO in plasma and the gastric headspace, respectively. Water-immersion-restraint stress (WIRS) increased myeloperoxidase (MPO) activity in gastric mucosa and induced hemorrhagic erosions by a nitrate-inhibitable mechanism. In animals that had received either cardiac ligation or oral treatment with povidone-iodine, a potent bactericidal agent, administration of nitrate failed to increase gastric levels of NO and to inhibit WIRS-induced mucosal injury. WIRS decreased gastric mucosal blood flow by a mechanism which was inhibited by administration of nitrate. These data suggested that the enterosalivary cycle of nitrate and related metabolites consisted of gastrointestinal absorption and salivary secretion of nitrate, its conversion to nitrite by oral bacteria and then to NO in the stomach might play important roles in the protection of gastric mucosa from hazardous stress.

  17. Effect of D-002 on gastric mucus composition in ethanol-induced ulcer.

    PubMed

    Carbajal, D; Molina, V; Noa, M; Valdés, S; Arruzazabala, M L; Aguilar, C; Más, R

    2000-10-01

    This study was designed to determine the effect of D-002, a natural product isolated and purified from beeswax (Apis mellifera), on gastric mucus composition on ethanol-induced ulcer in rats. The morphology of the lesions was analysed histologically, and morphometric analysis of gastric-gland content in total glycoprotein and sulphated macromolecules were done. Oral pretreatment with D-002 at 5 and 25 mgkg(-1)1 before oral administration of ethanol at 60%, produced a significant increase in the amount of gastric mucus and total protein. The histomorphometric evaluation of the gastric damage at the same doses showed a significant increase in neutral glycoproteins and sulfated macromolecules. It is concluded that enhancement of the quantity and quality of the mucus could partly explain the gastroprotective effect of D-002.

  18. Gastric mucosal damage induced by nonsalicylate nonsteroidal antiinflammatory drugs in rats is mediated systemically.

    PubMed

    Skeljo, M V; Giraud, A S; Yeomans, N D

    1993-11-01

    The gastric toxicities of an enteric-coated formulation and conventional indomethacin were compared in rats. Both formulations were equally damaging to the mucosa, suggesting that topical damage was not the major route of injury. The importance of systemically mediated damage was further determined by gastrotoxicity dose-response curves and pyloric ligation experiments in which indomethacin was administered either orally or parenterally, or into stomach or duodenum with the pylorus occluded. Gastric damage was significantly higher in those groups that had received the drug parenterally or intraduodenally. The extent of deeper mucosal damage, assessed histologically, was greater in parenterally dosed rats. In further experiments, oral and parenteral routes of administration of two other nonsalicylate NSAIDs, naproxen and sodium diclofenac, were found to be equally damaging to the mucosa. Our results show that indomethacin-induced gastric damage, unlike aspirin injury, is mediated mainly systemically. Enteric-coating may not be a useful strategy in reducing gastric injury by nonsalicylate, nonsteroidal antiinflammatory drugs.

  19. Endogenous histamine and promethazine-induced gastric ulcers in the guinea pig

    NASA Technical Reports Server (NTRS)

    Djahanguiri, B.; Hemmati, M.

    1978-01-01

    Experiments performed with an inhibitor of diaminoxydase, aminoguanidine and an inhibitor of histidine decarboxylase, NSD 1055, showed that the frequency of gastric ulcers induced by promethazine was increased with the first inhibitor and decreased with the second. It is suggested that ulcers induced by promethazine in guinea pigs might be due to histamino-liberator effect of the antihistaminio compound.