Gastrin and colorectal cancer: A prospective study

Thorburn, Christine; Friedman, Gary D.; Dickinson, Chris J.; Vogelman, Joseph H.; Orentreich, Norman; Parsonnet, Julie

doi:10.1016/s0016-5085(98)70193-3

Cited by 244 publications

(178 citation statements)

References 36 publications

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“…54 In certain disease states, such as Zollinger-Ellison syndrome, elevated plasma levels of nonamidated gastrins have been measured 30,31,55 ; these elevated levels may result in a predisposition toward colonic malignancy in a subpopulation of patients who also are positive for other associated risk factors. Hypergastrinemia reportedly is associated with mitogenic effects on colorectal mucosae 56,57 and with an increased risk of colonic malignancy 57,58 in a subpopulation of patients. Thus, there is good reason to believe that in patients with hypergastrinemia, circulating PG may play an important role in the initial stages of colon carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Cobb

Wood

Ceci

et al. 2004

Cancer

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Charcot–Marie–Tooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.

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Section: Discussionmentioning

confidence: 99%

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Cobb

Wood

Ceci

et al. 2004

Cancer

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“…While Omeprazole-induced hypergastrinemia was unable to increase tumor incidence in a colon cancer model in rats (Penman et al, 1993;Pinson et al, 1995), it promoted the growth of colorectal adenocarcinoma in APC Min/ þ mice, associated with a significant decrease in survival, which was reversed by the antigastrin antibody, Gastrimmune (Watson and Smith, 2001). A recent epidemiological study showed that prolonged hypergastrinemia increased the relative risk of developing colon cancer by 3.3-fold (Thorburn et al, 1998). Transgenic mice overexpressing the amidated forms of gastrin showed increased proliferation and hypertrophy of gastric mucosa (Wang et al, 1996), which synergized with H. pylori infection and enhanced the development and progression of invasive gastric cancer .…”

Section: Introductionmentioning

confidence: 99%

Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells

et al. 2004

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Gastrin and its precursors promote proliferation in different gastrointestinal cells. Since mature, amidated gastrin (G-17) can induce cyclin D1, we determined whether G-17-mediated induction of cyclin D1 transcription involved Wnt signaling and CRE-binding protein (CREB) pathways. Our studies indicate that G-17 induces protein, mRNA expression and transcription of the G 1 -specific marker cyclin D1, in the gastric adenocarcinoma cell line AGSE (expressing the gastrin/cholecystokinin B receptor). This was associated with an increase in steadystate levels of total and nonphospho b-catenin and its nuclear translocation, indicating the activation of the Wnt-signaling pathway. In addition, G-17-mediated increase in cyclin D1 transcription was significantly attenuated by axin or dominant-negative (dn) T-cell factor 4(TCF4), suggesting crosstalk of G-17 with the Wnt-signaling pathway. Mutational analysis indicated that this effect was mediated through the cyclic AMP response element (CRE) (predominantly) and the TCF sites in the cyclin D1 promoter, which was also inhibited by dnCREB. Furthermore, G-17 stimulation resulted in increased CRE-responsive reporter activity and CREB phosphorylation, indicating an activation of CREB. Chromatin immunoprecipitation studies revealed a G-17-mediated increase in the interaction of b-catenin with cyclin D1 CRE, which was attenuated by dnTCF4 and dnCREB. These results indicate that G-17 induces cyclin D1 transcription, via the activation of b-catenin and CREB pathways.

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“…However, in addition to its recognised role in the physiological regulation of acid secretion, another biological property attributed to gastrin is its trophic effects. A prospective study by Thorburn et al (1998) suggested that hypergastrinemia is associated with an increased risk for colorectal cancer (CRC), and numerous studies have demonstrated that gastrin stimulates the growth of malignant colorectal adenocarcinomas (Wang et al, 1996;Malecka-Panas et al, 1997;Baldwin & Shulkes, 1998;Nakata et al, 1998;Koh et al, 1999;Stepan et al, 1999;Smith & Watson, 2000). Transgenic mice overexpressing progastrin and glycine-extended gastrin demonstrate enhanced colonic proliferation (Wang et al, 1996;Koh et al, 1999), and conversely, gastrin-deficient mice manifest decreased colonic proliferation (Koh et al, 1997).…”

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confidence: 99%

Gastrin stabilises β-catenin protein in mouse colorectal cancer cells

et al. 2005

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As gastrin may play a role in the pathophysiology of gastrointestinal (GI) malignancies, the elucidation of the mechanisms governing gastrin-induced proliferation has recently gained considerable interest. Several studies have reported that a large percentage of colorectal tumours overexpress or stabilise the b-catenin oncoprotein. We thus sought to determine whether gastrin might regulate b-catenin expression in colorectal tumour cells. Amidated gastrin-17 (G-17), one of the major circulating forms of gastrin, not only enhanced b-catenin protein expression, but also one of its target genes, cyclin D1. Furthermore, activation of b-catenin-dependent transcription by gastrin was confirmed by an increase in LEF-1 reporter activity, as well as enhanced cyclin D1 promoter activity. Finally, G-17 prolonged the t 1/2 of b-catenin protein, demonstrating that gastrin appears to exert its mitogenic effects on colorectal tumour cells, at least in part, by stabilising b-catenin.

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Gastrin and colorectal cancer: A prospective study

Cited by 244 publications

References 36 publications

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells

Gastrin stabilises β-catenin protein in mouse colorectal cancer cells

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