Achlorhydria is associated with gastric microbial overgrowth and development of cancer: Lessons learned from the gastrin knockout mouse

Friis‐Hansen, Lennart

doi:10.1080/00365510600873894

Cited by 31 publications

(27 citation statements)

References 118 publications

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“…miR-24 is likely to predominantly operate by inhibiting translation. In addition, alkalization of the environment around the gastric epithelium may also take part in the induction of AE1 expression (Friis-Hansen, 2006). These data provide new insights into the molecular mechanisms of human erythropoiesis and gastric tumorigenesis.…”

Section: Discussionmentioning

confidence: 86%

Induction of anion exchanger-1 translation and its opposite roles in the carcinogenesis of gastric cancer cells and differentiation of K562 cells

Zhang

et al. 2010

Oncogene

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Anion exchanger-1 (AE1), an erythroid-specific membrane protein, mediates the Cl À /HCO À 3 exchange across the plasma membrane and regulates intracellular pH. We have found that AE1 was unexpectedly expressed in gastric cancer cells and participated in the tumorigenesis of the cancer. Here, we focus on the induction of AE1 expression and its role in gastric carcinogenesis as well as in the differentiation of K562 cells. The results show that expression of AE1 is not related to genetic mutation or the mRNA level, but rather, that it is modulated by miR-24. miR-24 decreases the expression of AE1 through binding to the 3 0 UTR of AE1 mRNA. Transfection of an miR-24 into gastric cancer cells reduced the elevation of the AE1 protein, which resulted in return of AE1-sequestrated p16 to the nucleus, thereby inhibiting proliferation of the cells. Furthermore, the miR-24 inhibitor cooperated with hemin to induce the expression of AE1 in K562 cells and differentiation of the cells, which is consistent with results obtained from the cells cultured at pH 7.6 or from forced stable expression of AE1. These findings establish a novel regulation of miR-24-related AE1 expression in gastric carcinogenesis and erythropoiesis.

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Section: Discussionmentioning

confidence: 86%

Induction of anion exchanger-1 translation and its opposite roles in the carcinogenesis of gastric cancer cells and differentiation of K562 cells

Zhang

et al. 2010

Oncogene

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“…41 Analogous to the studies in mice, hypochlorhydria in human patients with atrophic gastritis or following an antrectomy has also been reported result in an increased risk for developing gastric cancer, with most of the risk attributed to bacterial overgrowth as well as generation of carcinogenic substances such as N-nitrosamines, which can be found in increased amounts in hypochlorhydric patients. 42,43 We also recently reported that antibiotics treatment of H. pylori infected INS-GAS mice on an FVB/N background had an effect on arresting progression of gastric lesions. 18 Overall, the data taken together are consistent with a model in which gastrin serves as a rheostat for the stomach.…”

Section: Discussionmentioning

confidence: 89%

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

Takaishi

Dubeykovskaya

et al. 2009

The American Journal of Pathology

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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 Helicobacterassociated 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 wildtype 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. Gastric cancer remains the second leading cause of cancer-related mortality in the world, although its incidence and mortality rates have been decreasing in the United States over the past 70 years.

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“…Gastrin-deficient mice develop antral adenocarcinomas [46] through a mechanism that must be different from carcinogenesis in the oxyntic mucosa in hypoacidic and hypergastrinemic mice. The development of carcinomas in the absence of gastrin is attributed to bacterial overgrowth and subsequent formation of carcinogenic substances [47,48] . However, gastric hypoacidity is also found in H + K + ATPase-deficient mice which do not develop antral carcinomas (Fossmark R et al unpublished observations) and it is possible the lack of gastrin itself induces the carcinomas.…”

Section: Neoplasiamentioning

confidence: 99%

Gastric cancer: Animal studies on the risk of hypoacidity and hypergastrinemia

Fossmark

Qvigstad²

2008

WJG

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Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.

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Achlorhydria is associated with gastric microbial overgrowth and development of cancer: Lessons learned from the gastrin knockout mouse

Cited by 31 publications

References 118 publications

Induction of anion exchanger-1 translation and its opposite roles in the carcinogenesis of gastric cancer cells and differentiation of K562 cells

Induction of anion exchanger-1 translation and its opposite roles in the carcinogenesis of gastric cancer cells and differentiation of K562 cells

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

Gastric cancer: Animal studies on the risk of hypoacidity and hypergastrinemia

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