Glycine-Extended Gastrin Promotes the Invasiveness of Human Colon Cancer Cells

doi:10.1006/bbrc.2001.5132

Biochemical and Biophysical Research Communications

Volume 285, Issue 1, 6 July 2001, Pages 136-141

https://doi.org/10.1006/bbrc.2001.5132 Get rights and content

Abstract

Colorectal cancers express significant amounts of immature glycine-extended gastrin (G-Gly) and G-Gly is able to stimulate cell proliferation in colonic cell lines and mucosa. Here we wished to investigate whether G17-Gly promote the invasiveness of LoVo human colonic cancer cells, a process which requires degradation of extracellular matrix by proteases and concomitant induction of cell migration. We confirmed that LoVo cells express gastrin and gastrin/CCK-B receptor mRNAs. We showed that these cells secrete matrix metalloproteinase (MMP)-1, -2, and -9. The function of MMP being to degrade components of extracellular matrix, they may thus favor cell migration. As compared to controls, G17-Gly (10⁻⁷ to 10⁻¹² M) significantly enhanced about two to three times the LoVo cell migration through Matrigel, an artificial basement matrix barrier. Moreover, G17-Gly increased and gastrin/CCK-B receptor antagonists decreased MMP secretion in conditioned culture media of LoVo cells. Our findings show that physiological doses of incompletely processed form of gastrin induce the invasiveness of tumor cells in vitro and suggest a novel potential role for this peptide in the metastatic process of colonic cancers in vivo.

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Cited by (62)

Gastrin mediates resistance to hypoxia-induced cell death in xenografts of the human colorectal cancer cell line LoVo
2014, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
Whereas Gamide acts via the cholecystokinin 2 receptor (CCK2R) [6], the biological activity of PG and Ggly is not blocked by CCK2R antagonists [20]. Non-amidated gastrin precursors exert a spectrum of biological effects on a variety of human CRC cell lines in vitro [21–23], and down-regulation of endogenous gastrin expression suppressed xenograft tumourigenesis in three human CRC cell lines (DLD-1, HCT116 and SW480) that express high concentrations of PG and Ggly and low concentrations of Gamide [15,17,24]. Data regarding the interplay between hypoxia and gastrin are limited.
Aim: Gastrins act as growth factors for the normal and neoplastic colorectal mucosa. The aim of this study was to determine the role of gastrins in the response of human colorectal cancer (CRC) cells to hypoxia in vitro and in vivo. Methods: Expression of the gastrin gene in the human CRC cell line LoVo was examined under normoxia and hypoxia by quantitative PCR and by radioimmunoassay. Gastrin expression was knocked down with shRNA, and the effect on cell proliferation was measured by cell counting, on cell apoptosis by annexin V staining, and on cell migration by Boyden chamber assay. The effect of gastrin knockdown on tumourigenesis in mouse xenografts was analysed by measurement of tumour volumes and weights, and by immunohistochemistry. Results: Gastrin gene expression in LoVo cells was stimulated by hypoxia via binding of hypoxia-inducible factor-1α to the gastrin promoter. The viability of gastrin knockdown cells exposed to hypoxia (1% O₂) in vitro was diminished because of loss of resistance against hypoxia-induced apoptosis, and the effect was partly reversed by treatment with non-amidated, but not amidated, gastrin. Conditioned medium from control LoVo cells under hypoxia simulated proliferation but not migration, and the effect was blocked by an inhibitor of non-amidated gastrins, but not by an inhibitor of amidated gastrins. In xenografts in mice exposed to hypoxia (10% O₂) for 21 days, tumour necrosis was significantly increased by knocking down gastrin expression. Conclusion: These results provide evidence that non-amidated gastrins are involved in the adaptation of CRCs to hypoxic microenvironments through increasing resistance to apoptosis.
Adiponectin inhibits leptin-induced oncogenic signalling in oesophageal cancer cells by activation of PTP1B
2014, Molecular and Cellular Endocrinology
Obesity is characterised by hyperleptinaemia and hypoadiponectinaemia and these metabolic abnormalities may contribute to the progression of several obesity-associated cancers including oesophageal adenocarcinoma (OAC). We have examined the effects of leptin and adiponectin on OE33 OAC cells. Leptin stimulated proliferation, invasion and migration and inhibited apoptosis in a STAT3-dependant manner. Leptin-stimulated MMP-2 secretion in a partly STAT3-dependent manner and MMP-9 secretion via a STAT3-independent pathway. Adiponectin inhibited leptin-induced proliferation, migration, invasion, MMP secretion and reduced the anti-apoptotic effects: these effects of adiponectin were ameliorated by both a non-specific tyrosine phosphatase inhibitor and a specific PTP1B inhibitor. Adiponectin reduced leptin-stimulated JAK2 activation and STAT3 transcriptional activity in a PTP1B-sensitive manner and adiponectin increased both PTP1B protein and activity. We conclude that adiponectin restrains leptin-induced signalling and pro-carcinogenic behaviour by inhibiting the early events in leptin-induced signal transduction by activating PTP1B. Relative adiponectin deficiency in obesity may contribute to the promotion of OAC.
Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer
2012, Surgical Oncology
Citation Excerpt :
Autocrine activation of these CCK2R/GR variants showed increase in-vitro growth and tumourigenicity of non-tumourigenic colon epithelial cells [165] supporting the hypothesis that expression of Gs and its receptors in human colonic adenomas contributes to tumour growth and progression. Autocrine production of Gs/CCK-like peptide were also reported in colon cancer that stimulate hyperproliferation and invasiveness of tumour cells, thus these play a novel potential role in the metastatic process of colonic cancers [58,170,171]. Inhibition of colon cancer growth by CCK2R/GR antagonist [172,173] and gastrimmune raised antibodies [174] have suggested that hormone based therapy with CCK2R/GR antagonist and targeting of the CCK2R/GR could be employed for treatment and diagnosis of these cancer [63,171,175] However, other study has demonstrated use of CCK1R antagonists in controlling colon cancer cell growth [176].
Cholecystokinin and Gastrin are amongst the first gastrointestinal hormone discovered. In addition to classical actions (contraction of gallbladder, growth and secretion in the stomach and pancreas), these also act as growth stimulants for gastrointestinal malignancies and cell lines. Growth of these tumours is inhibited by antagonists of the cholecystokinin and gastrin receptors. These receptors provides most promising approach in clinical oncology and several specific radiolabelled ligands have been synthesized for specific tumour targeting and therapy of tumours overexpressing these receptors. Therefore, definition of the molecular structure of the receptor involved in the autocrine/paracrine loop may contribute to novel therapies for gastrointestinal cancer. Hence, this review tries to focus on the role and distribution of these hormones and their receptors in gastrointestinal cancer with a brief talk about the clinical trial using available agonist and antagonist in gastrointestinal cancers.
Gastrins, iron homeostasis and colorectal cancer
2011, Biochimica et Biophysica Acta - Molecular Cell Research
The peptide hormone gastrin has been identified as a major regulator of acid secretion and a potent mitogen for normal and malignant gastrointestinal cells. The importance of gastric acid in the absorption of dietary iron first became evident 50 years ago when iron deficiency anemia was recognized as a long-term consequence of partial gastrectomy. This review summarizes the connections between circulating gastrins, iron status and colorectal cancer. Gastrins bind two ferric ions with micromolar affinity and, in the case of non-amidated forms of the hormone, iron binding is essential for biological activity in vitro and in vivo. The demonstration of an interaction between gastrin and transferrin by biochemical techniques led to the proposal that gastrins catalyze the loading of transferrin with iron. Several lines of evidence, including the facts that the concentrations of circulating gastrins are increased in mice and humans with the iron overload disease hemochromatosis and that transferrin saturation positively correlates with circulating gastrin concentration, suggest the potential involvement of gastrins in iron homeostasis. Conversely, recognition that ferric ions play an unexpected role in the biological activity of gastrins may assist in the development of useful therapies for colorectal carcinoma and other disorders of mucosal proliferation in the gastrointestinal tract.
Gastrin increases its own synthesis in gastrointestinal cancer cells via the CCK2 receptor
2010, FEBS Letters
The involvement of the gastrointestinal hormone gastrin in the development of gastrointestinal cancer is highly controversial. Here we demonstrate a positive-feedback loop whereby gastrin, acting via the CCK2 receptor, increases its own expression. Such an autocrine loop has not previously been reported for any other gastrointestinal hormone. Gastrin promoter activation was dependent on the MAP kinase pathway and did not involve Sp1 binding sites or epidermal growth factor receptor transactivation. As the treatment of gastrointestinal cancer cells with amidated gastrin led to increased expression of non-amidated gastrins, the positive-feedback loop may contribute to the sustained increase in circulating gastrins observed in colorectal cancer patients.
Gastrointestinal Hormones and Tumor Syndromes
2010, Endocrinology: Adult and Pediatric, Sixth Edition

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Regular ArticleGlycine-Extended Gastrin Promotes the Invasiveness of Human Colon Cancer Cells

Abstract

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Matrix Biol.

Gastroenterology

Identification of progastrin-derived peptides in colorectal carcinoma extracts

Gut

Incomplete processing of progastrin expressed by human colon cancer cells: Role of noncarboxyamidated gastrins

Am. J. Physiol.

Gastrin and gastrin receptor activation: An early event in the adenoma-carcinoma sequence

Gut

Chronic endogenous gastrin hypergastrinemia in humans: Evidence for a mitogenic effect on the colonic mucosa

Gastroenterology

New aspects of the trophic actions of gastrointestinal hormones

Gastroenterology

Gastrin and colorectal cancer: A never-ending dispute?

Gastroenterology

Prolonged hypergastrinemia does not increase the frequency of colonic neoplasia in patients with the Zollinger-Ellison syndrome

Dig. Dis. Sci.

Regular Article
Glycine-Extended Gastrin Promotes the Invasiveness of Human Colon Cancer Cells