Down‐regulation of a morphogen (sonic hedgehog) gradient in the gastric epithelium of <i>Helicobacter pylori</i>‐infected Mongolian gerbils

Suzuki, Hidekazu; Minegishi, Yuriko; Nomoto, Y.; Ota, Takayuki; Masaoka, Tatsuhiro; Brink, Gijs R. van den; Hibi, Toshifumi

doi:10.1002/path.1763

Cited by 68 publications

(87 citation statements)

References 26 publications

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“…Substantial evidence has shown that the Shh pathway is crucial to the development and homeostasis of gastric glands. In addition, abnormal activation of the Shh pathway has been found toresult in gastric cancer (12)(13)(14).The aim of the present study was to investigate the effects of metformin on the regulation of the Shh signaling pathway in gastric cancer cells. The expression levels of Shh, Glioma associated oncogene (Gli)-1, Gli-2 and Smoothened (SMO) were examined using western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses.…”

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confidence: 95%

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Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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Abstract. The traditional anti-diabetic drug, metformin, has been found to have anticancer effects. The Sonic hedgehog (Shh) signaling pathway is involved in the on cogenesis of gastric cancer. The aim of the present study was to investigate whether metformin has an effect on the Shh signaling pathway in gastric cancer cells. HGC-27 and MKN-45 human gastric cancer cells were treated with metformin at different concentrations and for different durations. Subsequently the mRNA and protein levels of Shh, Smoothened (SMO), and Glioma-associated oncogene (Gli)-1, Gli-2 and Gli-3 were examined using western blot and reverse transcription-quantitative polymerase chain reaction analyses. RNA interference was used to detect whether the effects of metformin treatment on the Shh signaling pathway were dependent on AMP-activated protein kinase (AMPK). The results revealed that the protein and mRNA levels of Shh and Gli-1 were decreased by metformin treatment in the two cell lines in a dose-and time-dependent manner. Metformin also significantly inhibited the gene and protein expression levels of SMO, Gli-2 and Gli-3. The small interfering RNA-induced depletion of AMPK reversed the suppressive effect of metformin on recombinant human Shh-induced expression of Gli-1 in HGC-27 gastric cancer cells. Therefore, metformin inhibited the Shh signaling pathway in the gastric cancer cell lines and the inhibitory effect of metformin on the Shh pathway was AMPK-dependent. IntroductionGastric cancer is one of the most common types of malignant cancer worldwide (1). In addition tosurgery, chemotherapy and radio chemotherapy, there is a demand for novel treatment approaches for gastric cancer due to its poor prognosis (2).Metformin is a widely used anti-diabetic drug, which has been reported to exhibit potential anticancer activity (3). Previous studies have shown that metformin administration significantly reduces the incidence and mortality rates of various types of cancer, including gastric cancer (4-6). According to the findings reported by a previous study, patients who were treated with metformin hada lower incidence of gastric cancer, compared with those who did not receive metformin treatment (7). However, the mechanism underlying the anticancer effects of metformin is complex and remains to be fully elucidated. Activation of the AMP-activated protein kinase (AMPK) pathway has been recognized as a key aspect of the anticancer effects of metformin (8).The Sonic hedgehog (Shh) signaling pathway is one of the most common signal transduction pathways in human cells (9). It is critical in normal cell differentiation and embryonic development (10). However, abnormal activation of the Shh pathway has been identified in several types of human cancer (11). Substantial evidence has shown that the Shh pathway is crucial to the development and homeostasis of gastric glands. In addition, abnormal activation of the Shh pathway has been found toresult in gastric cancer (12)(13)(14).The aim of the present study was to investigate the effects of m...

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confidence: 95%

Section: Introductionmentioning

confidence: 99%

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

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“…In the claudin‐18‐KO mouse, acid backflux from the gland lumen also causes parietal cell loss, but this occurs within the first days of life 10. A similar, albeit delayed, parietal cell loss followed by fundic hyperplasia and inflammatory cell infiltration occurs in the occludin‐KO mouse 36, 43. In the CAIX‐KO gastric mucosa, the only significant abnormality detected by us at one month of age was an increase in the gastric mucosal IL‐1 β and iNOS expression, and the strong decrease in claudin‐18 expression (Figs 5 and 6).…”

Section: Discussionmentioning

confidence: 95%

Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin‐18 downregulation and acid backflux

Liu

Riederer

et al. 2017

Acta Physiologica

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AimThis study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX).MethodsWe assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH i of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR.Results CAIX‐knockout gastric surface epithelial cells showed significantly faster pH i decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months.ConclusionsWe propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO 2 and H2O, contributing to tight junction protection and gastric epithelial pH i regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.

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“…As for unsolved questions that how hypertrophic gastritis develops under the prominent pathological background of atrophic gastritis associated with H. pylori infection [4] or how the attenuated levels of sonic hedgehog (Shh) observed up to the development of precancerous lesions turned into increased expressions in gastric cancer [12,13], we speculates two possibilities; one is the emergence or reactivation of cell clones harboring apoptosis resistant characteristics even under prevailing apoptosis after H. pylori infection and the other is the enormous expansion of cell clone possessing proliferative properties.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, all of these cancers arise from the tissues where Shh signaling plays an important developmental role. Since the loss of Shh is an indicator of H. pylori-induced atrophic gastritis mechanistically through either promoter methylation or loss of Shh expressing cells by gastric inflammation and increased expression of Shh was noted in gastric cancer [13,14], we hypothesized that the reemergence of cell clones carrying Shh after H. pylori infection might contribute to the resistance to apoptosis, providing the chance to proliferative activities under the milieu of H. pylori-induced atrophic gastritis.…”

Section: Introductionmentioning

confidence: 99%