Role of gastrin peptides in carcinogenesis

Grabowska, Anna; Watson, Susan A.

doi:10.1016/j.canlet.2007.06.017

Cited by 45 publications

(28 citation statements)

References 138 publications

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“…Gastrin has been implicated in a number of human disease states, e.g., chronic gastritis and gastrointestinal cancers [30][31][32][33] . Presumably this is due to aberrant regulation of gastrin gene expression.…”

Section: Discussionmentioning

confidence: 99%

Regulated expression of the human gastrin gene in mice

Mensah-Osman

Labut

Zavros

et al. 2008

Regulatory Peptides

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Gastrin is secreted from neuroendocrine cells residing in the adult antrum called G cells, but constitutively low levels are also expressed in the duodenum and fetal pancreas. Gastrin normally regulates gastric acid secretion by stimulating the proliferation of enterochromaffin-like cells and the release of histamine. Gastrin and progastrin forms are expressed in a number of pathological conditions and malignancies. However, the DNA regulatory elements in the human versus the mouse gastrin promoters differ suggesting differences in their transcriptional control. Thus, we describe here the expression of the human gastrin gene using a bacterial artificial chromosome (BAC) in the antral and duodenal cells of gastrin null mice. All 5 founder lines expressed the 253 kb human gastrin BAC. hGasBac transgenic mice were bred onto a gastrin null background so that the levels of human gastrin peptide could be analyzed by immunohistochemistry and radioimmunoassay without detecting endogenous mouse gastrin. We have shown previously that chronically elevated gastrin levels suppress somatostatin. Indeed, infusion of amidated rat gastrin depressed somatostatin levels, stimulated gastric acid secretion and an increase in the numbers of G cells in the antrum and duodenum. In conclusion, human gastrin was expressed in mouse enteroendocrine cells and was regulated by somatostatin. This mouse model provides a unique opportunity to study regulation of the human gastrin promoter in vivo by somatostatin and possibly other extracellular regulators contributing to our understanding of the mechanisms involved in transcriptional control of the human gene.

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Section: Discussionmentioning

confidence: 99%

Regulated expression of the human gastrin gene in mice

Mensah-Osman

Labut

Zavros

et al. 2008

Regulatory Peptides

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“…CCK2R expression may also be coupled with the coexpression of gastrin and CCK in different human tumors and cancer cell lines. A permanent activation of the CCK2R by a gastrin/CCK-CCK2R autocrine loop has been reported to promote cell growth in different tumor cells ( 4,(14)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion

Paillasse

Médina

Amouroux

et al. 2009

Journal of Lipid Research

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“…17 Another physiologic role of gastrin is in regulating the proliferation of gastric mucosal cells which has led to investigations into its effects on stimulating tumor cell growth. 18 It has been reported that gastrin plays a role in gastric cancer development. 19 Overexpression of human gastrin in specific transgenic animals leads to the development of precancerous conditions identified by histopathology, immunohistochemistry and biomolecular technology.…”

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confidence: 99%

Gastrin suppresses the interdependent expression of p16 and anion exchanger 1 favoring growth inhibition of gastric cancer cells

Tian

Zhang

Suo

et al. 2010

Intl Journal of Cancer

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Our previous studies demonstrated that expression and interaction of p16 with anion exchanger 1 (AE1) in gastric cancer cells is correlated with progression and shorter survival of the cancer. In this article, the effects of gastrin on p16 and AE1 and its implication in prevention and treatment of gastric cancer were studied by molecular biology techniques, animal experiment and clinical analysis. The results showed that expression of p16 in human gastric body carcinoma was downregulated along with the progression of the cancer, suggesting the reverse correlations between gastrin and p16 in vivo. Further experiments indicated that gastrin suppressed the expression of p16 via the p16 promoter and thereafter resulted in the degradation of AE1 in gastric cancer cells. Silencing of AE1 or p16 significantly inhibited the proliferation of the cancer cells. Using a xenograft tumor model in nude mice, we showed that experimental systemic hypergastrinemia induced by the administration of omeprazole led to decreased expression of AE1 and p16 as well as to a marked growth inhibition of SGC7901 tumors. It is concluded that a moderate plasma gastrin level is beneficial to the growth inhibition of gastric cancer by suppressing the expression of AE1 and p16. This finding may have an important implication for the prevention and treatment of cancers arise in the gastric antrum.Anion exchanger 1 (AE1) is abundantly expressed in erythrocytes and efficiently contributes to intracellular pH regulation and homeostasis of erythrocytes by catalyzing the reversible exchange of Cl À /HCO À 3 across the plasma membrane. 1,2Structural analysis has revealed that AE1 consists of a N-terminal cytoplasmic domain, a multispanning membrane domain and an acidic short C-terminal cytoplasmic domain. 3The C-terminal region of AE1 contains the binding sites for tumor suppressor p16, which has been reported in our previous paper. 4The p16 negatively regulates the cell cycle. Abnormal expression of p16 has been demonstrated in a variety of cancer cells.5-8 Functional inactivation of the p16 gene induced by several factors has been shown in many different types of human carcinomas.9-11 However, recent studies revealed that overexpression of the p16 protein in cytoplasm of cancer cells is associated with the tumor progression and poor prognosis, suggesting that cytoplasmic distribution of p16 might indicate an inactive form of the protein. [12][13][14][15] Our previous studies demonstrated that expression and interaction of p16 with AE1 in gastric cancer cells is correlated with progression and shorter survival of the cancer.12,16 Thus, how AE1/p16 becomes involved in the carcinogenesis of gastric cancer needs further elucidation.Gastrin is expressed primarily in G cells located in the gastric antrum and to a lesser in the duodenum and is involved in gastric acid production. 17 Another physiologic role of gastrin is in regulating the proliferation of gastric mucosal cells which has led to investigations into its effects on stimulating tumor cell growth.1...

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Role of gastrin peptides in carcinogenesis

Cited by 45 publications

References 138 publications

Regulated expression of the human gastrin gene in mice

Regulated expression of the human gastrin gene in mice

Signaling through cholesterol esterification: a new pathway for the cholecystokinin 2 receptor involved in cell growth and invasion

Gastrin suppresses the interdependent expression of p16 and anion exchanger 1 favoring growth inhibition of gastric cancer cells

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