Gene Summary

Gene:CCKBR; cholecystokinin B receptor
Aliases: GASR, CCK-B, CCK2R
Summary:This gene encodes a G-protein coupled receptor for gastrin and cholecystokinin (CCK), regulatory peptides of the brain and gastrointestinal tract. This protein is a type B gastrin receptor, which has a high affinity for both sulfated and nonsulfated CCK analogs and is found principally in the central nervous system and the gastrointestinal tract. Alternative splicing results in multiple transcript variants. A misspliced transcript variant including an intron has been observed in cells from colorectal and pancreatic tumors. [provided by RefSeq, Dec 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:gastrin/cholecystokinin type B receptor
Source:NCBIAccessed: 09 March, 2017


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 10 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CCKBR (cancer-related)

Rai R, Kim JJ, Tewari M, Shukla HS
Heterogeneous expression of cholecystokinin and gastrin receptor in stomach and pancreatic cancer: An immunohistochemical study.
J Cancer Res Ther. 2016 Jan-Mar; 12(1):411-6 [PubMed] Related Publications
AIM: Cholecystokinin (CCK) and gastrin (Gs) are a well known trophic factor for the gastrointestinal tract and their trophic effects are shown mainly toward pancreas and stomach, respectively. Though, the exact characterization of CCK and Gs receptors subtype (cholecystokinin type A receptor [CCKAR] and cholecystokinin type B receptor/gastrin receptor [CCKBR/GR]) in stomach cancer (SC) and pancreatic cancer (PC) is still controversial and necessities further validation.
SUBJECTS AND METHODS: CCKAR and CCKBR/GR expression was analyzed by immunohistochemistry in 55 SC, 25 benign gastric diseases (BGDs), 38 PC (including periampullary carcinoma), and 10 normal pancreatic tissue. The results were statistically correlated with the patient's clinical history to observe the prognostic significance if any.
RESULT: CCKAR expression was detected in 18.2% of SC, 20% of BGD, 65.8% of PC, and 30.0% of normal pancreas tissue samples. The CCKBR/GR expression was detected in 58.2% of SC, 48.0% of BGD, 18.4% of PC, and 60.0% of normal pancreas tissue samples. CCKBR/GR expression was significantly high in well and moderately differentiated SC samples as compared to poorly differentiated samples.
CONCLUSION: Our study showed significantly higher expression of CCKAR and down regulation of CCKBR in PC as compared to control while CCKBR/GR was detected in majority of SC samples. Thus, our study suggests that CCK and Gs receptors may have diagnostic and therapeutic implications. However, study need to be validated in significantly bigger sample size and need to be replicated in different cohorts.

Balázs A, Németh BC, Ördög B, et al.
A Common CCK-B Receptor Intronic Variant in Pancreatic Adenocarcinoma in a Hungarian Cohort.
Pancreas. 2016; 45(4):541-5 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
OBJECTIVES: Variant c.811+32C>A in intron 4 of the cholecystokinin-B receptor gene (CCKBR) was reported to correlate with higher pancreatic cancer risk and poorer survival. The variant was suggested to induce retention of intron 4, resulting in a new splice form with enhanced receptor activity. Our objective was to validate the c.811+32C>A variant as an emerging biomarker for pancreatic cancer risk and prognosis.
METHODS: We genotyped variant c.811+32C>A in 122 pancreatic adenocarcinoma case patients and 106 control subjects by sequencing and examined its association with cancer risk and patient survival. We tested the functional effect of variant c.811+32C>A on pre-messenger RNA splicing in human embryonic kidney 293T and Capan-1 cells transfected with CCKBR minigenes.
RESULTS: The allele frequency of the variant was similar between patients and control subjects (18.4% and 17.9%, respectively). Survival analysis showed no significant difference between median survival of patients with the C/C genotype (266 days) and patients with the A/C or A/A genotypes (257 days). CCKBR minigenes with or without variant c.811+32C>A exhibited no difference in expression of the intron-retaining splice variant.
CONCLUSION: These data indicate that variant c.811+32C>A in CCKBR does not have a significant impact on pancreatic cancer risk or survival in a Hungarian cohort.

Cui Y, Li SB, Peng XC, et al.
Trastuzumab Inhibits Growth of HER2-Negative Gastric Cancer Cells Through Gastrin-Initialized CCKBR Signaling.
Dig Dis Sci. 2015; 60(12):3631-41 [PubMed] Related Publications
BACKGROUND: Administration of trastuzumab, a fully humanized monoclonal antibody targeted to the human epidermal growth factor receptor 2 (HER2, p185), has improved outcomes for patients with HER2-positive gastric cancer (GC), but some relevant issues remain to be investigated and will emerge with new anti-GC drugs. Gastrin is a major gastrointestinal hormone proven to have an inhibitory effect on GC in vitro and in vivo.
AIM: To explore the sympathetic role of trastuzumab and gastrin on inhibition of GC.
METHODS: The HER2-positive and HER2-negative GC cell lines were treated with trastuzumab, gastrin, or their combination in vitro and in xenograft model. The synergistical role of trastuzumab and gastrin and related mechanisms were investigated.
RESULTS: We found the synergistic inhibitory effects of trastuzumab and gastrin on HER2-negative GC cells through the gastrin/cholecystokinin B receptor (CCKBR) pathway. Trastuzumab upregulated CCKBR protein levels but could not initiate its signal transduction, whereas gastrin increased the levels and activation of CCKBR. Molecular experiments indicated that trastuzumab and gastrin co-treatment synergistically enhanced the stability of CCKBR. Moreover, their combined treatment synergistically arrested GC cells at G0/G1 phase, down-regulated levels of GC-related proteins, including anion exchanger 1 (AE1), cyclin D1, β-catenin, and cytoplasmic p16, and promoted nuclear translocation of p16. In addition, combination treatment upregulated AE2 levels, which are reduced in GC tissues. The in vivo synergistic anti-GC effect of combined treatment was confirmed in xenograft experiments.
CONCLUSIONS: Trastuzumab plus gastrin inhibit growth of Her2-negative GC by targeting cytoplasmic AE1 and p16.

Kaloudi A, Nock BA, Krenning EP, et al.
Radiolabeled gastrin/CCK analogs in tumor diagnosis: towards higher stability and improved tumor targeting.
Q J Nucl Med Mol Imaging. 2015; 59(3):287-302 [PubMed] Related Publications
Cholecystokinin subtype 2 receptors (CCK2R) are overexpressed in several human cancers, including medullary thyroid carcinoma. Gastrin and cholecystokinin (CCK) peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing tumor sites. Several gastrin and CCK related peptides have been proposed for diagnostic imaging and radionuclide therapy of primary and metastatic CCK2R-positive human tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises tumor uptake. This problem has been addressed by structural modifications of gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major enzyme implicated in the catabolism of gastrin and CCK based peptides is neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor phosphoramidon (PA) with radiolabeled gastrin and other peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and tumor-localization of radiopeptides in tumor sites. Specifically, co-administration of PA with the truncated gastrin analog [(111)In-DOTA]MG11 ([((111)In-DOTA)DGlu(10)]gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive tumor uptake in SCID mice. This increased tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled gastrin analogs in CCK2R-expressing cancer patients.

Kim O, Yoon JH, Choi WS, et al.
Gastrokine 1 inhibits gastrin-induced cell proliferation.
Gastric Cancer. 2016; 19(2):381-91 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: Gastrokine 1 (GKN1) acts as a gastric tumor suppressor. Here, we investigated whether GKN1 contributes to the maintenance of gastric mucosal homeostasis by regulating gastrin-induced gastric epithelial cell growth.
METHODS: We assessed the effects of gastrin and GKN1 on cell proliferation in stable AGS(GKN1) and MKN1(GKN1) gastric cancer cell lines and HFE-145 nonneoplastic epithelial cells. Cell viability and proliferation were analyzed by MTT and BrdU incorporation assays, respectively. Cell cycle and expression of growth factor receptors were examined by flow cytometry and Western blot analyses.
RESULTS: Gastrin treatment stimulated a significant time-dependent increase in cell viability and proliferation in AGS(mock) and MKN1(mock), but not in HFE-145, AGS(GKN1), and MKN1(GKN1), cells, which stably expressed GKN1. Additionally, gastrin markedly increased the S-phase cell population, whereas GKN1 significantly inhibited the effect of gastrin by regulating the expression of G1/S cell-cycle regulators. Furthermore, gastrin induced activation of the NF-kB and β-catenin signaling pathways and increased the expression of CCKBR, EGFR, and c-Met in AGS and MKN1 cells. However, GKN1 completely suppressed these effects of gastrin via downregulation of gastrin/CCKBR/growth factor receptor expression. Moreover, GKN1 reduced gastrin and CCKBR mRNA expression in AGS and MKN1 cells, and there was an inverse correlation between GKN1 and gastrin, as well as between GKN1 and CCKBR mRNA expression in noncancerous gastric mucosae.
CONCLUSION: These data suggest that GKN1 may contribute to the maintenance of gastric epithelial homeostasis and inhibit gastric carcinogenesis by downregulating the gastrin-CCKBR signaling pathway.

Wayua C, Low PS
Evaluation of a nonpeptidic ligand for imaging of cholecystokinin 2 receptor-expressing cancers.
J Nucl Med. 2015; 56(1):113-9 [PubMed] Related Publications
UNLABELLED: Tumor-specific targeting ligands were recently exploited to deliver both imaging and therapeutic agents selectively to cancer tissues in vivo. Because the cholecystokinin 2 receptor (CCK2R) is overexpressed in various human cancers (e.g., lung, medullary thyroid, pancreatic, colon, and gastrointestinal stromal tumors) but displays limited expression in normal tissues, natural ligands of CCK2R were recently explored for use in the imaging of CCK2R-expressing cancers. Unfortunately, the results from these studies revealed not only that the peptidic CCK2R ligands were unstable in vivo but also that the ligands that mediated good uptake by tumor tissues also promoted a high level of retention of the radioimaging agent in the kidneys, probably because of capture of the conjugates by peptide-scavenging receptors. In an effort to reduce the normal organ retention of CCK2R-targeted drugs, we synthesized a nonpeptidic ligand of CCK2R and examined its specificity for CCK2R both in vitro and in vivo.
METHODS: Nonpeptidic agonists and antagonists of CCK2R described in the literature were evaluated for their affinities and specificities for CCK2R. Z-360, a benzodiazepine-derived CCK2R antagonist with subnanomolar affinity, was selected for complexation to (99m)Tc via multiple spacers. After synthesis and purification, 4 complexes with different physicochemical properties were evaluated for binding to CCK2R-transfected HEK 293 cells. The best conjugate, termed CRL-3-(99m)Tc, was injected into mice bearing CCK2R tumor xenografts and examined by γ scintigraphy and SPECT/CT. The uptake of the conjugate in various organs was also quantified by tissue resection and γ counting.
RESULTS: CRL-3-(99m)Tc was shown to bind with low nanomolar affinity to CCK2R in vitro and was localized to tumor tissues in athymic nu/nu mice implanted with CCK2R-expressing tumors. At 4 h after injection, tumor uptake was measured at 12.0 ± 2.0 percentage injected dose per gram of tissue.
CONCLUSION: Because the uptake of CRL-3-(99m)Tc by nonmalignant tissues was negligible and retention in the kidneys was only transient, we suggest that CRL-3-(99m)Tc may be a useful radioimaging agent for the detection, sizing, and monitoring of CCK2R-expressing tumors.

Smith JP, Whitcomb DC, Matters GL, et al.
Distribution of cholecystokinin-B receptor genotype between patients with pancreatic cancer and controls and its impact on survival.
Pancreas. 2015; 44(2):236-42 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
OBJECTIVE: Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer through the CCK-B receptor (CCK-BR). A splice variant of the CCK-BR that results from a single nucleotide polymorphism (SNP) has been identified. Because the splice variant receptor has an extended third intracellular loop, an area involved in cell signaling and growth, we hypothesized that this genetic variant could contribute to the poor prognosis and short survival of this malignancy.
METHODS: DNA from 931 patients with pancreatic cancer was evaluated for the SNP (C > A; rs1800843) in the CCK-BR gene. For statistical analysis, the Fisher exact test was used to compare the genotype and allele frequency between the cancer cohort and normal controls and the dependence of genotype on factors, such as stage of disease and age, was analyzed using Cox proportional hazards models.
RESULTS: Compared to the normal cohort, the frequency of the A-allele in pancreatic cancer subjects was increased (P = 0.01123; odds ratio, 2.283). Even after adjustment for stage of disease, survival of subjects with the minor allele was significantly shorter than those with the wild-genotype (hazard ratio, 1.83; P = 3.11 × 10(-11)).
CONCLUSIONS: The CCK-BR SNP predicts survival and should be studied as a candidate genetic biomarker for those at risk of pancreatic cancer.

Theissen J, Oberthuer A, Hombach A, et al.
Chromosome 17/17q gain and unaltered profiles in high resolution array-CGH are prognostically informative in neuroblastoma.
Genes Chromosomes Cancer. 2014; 53(8):639-49 [PubMed] Related Publications
The prognostic relevance of chromosome 17 gain in neuroblastoma is still discussed. This investigation specifies the frequency, type, size, and transcriptional relevance in a large patient cohort. Primary tumor material of 202 patients was analyzed using high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH) and correlated with clinical and survival data. A subset (n = 145) was correlated for differentially expressed genes (DEG) by microarray analysis. Chromosome 17 aCGH analysis showed numerical gain in 94/202 patients (47%), partial gain in 93/202 patients (46%), and no gain in 15/202 patients (7%). The frequency of partial gain was higher in stage 4 neuroblastoma (stage 1 15%; stage 2 12%; stage 3 16%; stage 4S 7%; and stage 4 50%). Overall survival (OS) was superior in patients with numerical gain compared with patients with partial gain or no gain (5-y-OS: 0.95 ± 0.02 vs. 0.63 ± 0.05 vs. 0.60 ± 0.13; P < 0.001). Gene expression analysis demonstrated 95/130 DEGs between tumors with numerical or partial chromosome/no gain. Only one DEG (CCKBR) was detected comparing tumors with partial gain and those with no gain. In patients with partial gain, the distribution of breakpoints did not correlate with stage and 11q status, but with MYCN amplification and 1p status. The "best" breakpoints in cases with partial 17q gain were at 42.5 Mb for event-free and 26.6 Mb for OS. Numerical gain of chromosome 17 is associated with a better prognosis than partial and no gain. The group of tumors with partial gain was similar to the group without gain with respect to stage distribution, outcome, and gene expression profile.

He Y, Meng XM, Huang C, et al.
Long noncoding RNAs: Novel insights into hepatocelluar carcinoma.
Cancer Lett. 2014; 344(1):20-7 [PubMed] Related Publications
Recent advances in non-protein coding part of human genome analysis have discovered extensive transcription of large RNA transcripts that lack of coding protein function, termed long noncoding RNAs (lncRNAs). It is becoming evident that lncRNAs may be an important class of pervasive genes involved in carcinogenesis and metastasis. However, the biological and molecular mechanisms of lncRNAs in diverse diseases are not yet fully understood. Thus, it is anticipated that more efforts should be made to clarify the lncRNAs world. Moreover, accumulating studies have demonstrated that a class of lncRNAs are dysregulated in hepatocellular carcinoma(HCC) and closely related with tumorigenesis, metastasis, prognosis or diagnosis. In this review, we will briefly discuss the regulation and functional role of lncRNAs in HCC, therefore evaluating the potential of lncRNAs as prospective novel therapeutic targets in HCC.

Zhang R, Li M, Zang W, et al.
MiR-148a regulates the growth and apoptosis in pancreatic cancer by targeting CCKBR and Bcl-2.
Tumour Biol. 2014; 35(1):837-44 [PubMed] Related Publications
Our previous studies have revealed that miR-148a is downregulated in pancreatic cancer. Bioinformatics analysis has shown cholecystokinin-B receptor (CCKBR) and B cell lymphoma (Bcl-2) to be potential targets of miR-148a. But the pathophysiologic role of miR-148a and its relevance to the growth and development of pancreatic cancer are yet to be investigated. The purpose of this study is to elucidate the molecular mechanisms where miR-148a acts as a tumor suppressor in pancreatic cancer. Our results showed significant downregulation of miR-148a in 28 pancreatic cancer tissue samples and five pancreatic cancer cell lines, compared with their non-tumor counterparts by qRT-PCR. MiR-148a was found to not only inhibit the proliferation of pancreatic cancer cells (PANC-1 and AsPC-1) in vitro by MTT assay and colony formation assay, but also to promote cells apoptosis in vitro by Annexin V-FITC apoptosis detection and caspase activity assay. Using western blot and luciferase activity assay, CCKBR and Bcl-2 were identified as targets of miR-148a. Moreover, we also found that the expression of Bcl-2 lacking in 3'UTR could abrogate the pro-apoptosis function of miR-148a. These findings suggest the importance of miR-148a's targeting of CCKBR and Bcl-2 in the regulation of pancreatic cancer growth and apoptosis.

Goetze JP, Eiland S, Svendsen LB, et al.
Characterization of gastrins and their receptor in solid human gastric adenocarcinomas.
Scand J Gastroenterol. 2013; 48(6):688-95 [PubMed] Related Publications
OBJECTIVE: The gastrin and the gastrin/CCK-B receptor genes are co-expressed in several carcinomas. The primary translational product, progastrin, however, is processed to several peptides of which only those that are α-amidated at their C-terminus are receptor ligands. So far, characterization of the progastrin-derived peptides in gastric cancer has not been reported. The authors therefore examined the molecular nature of gastrin and its receptor in human gastric carcinomas.
MATERIALS AND METHODS: Twenty patients with adenocarcinoma underwent partial or total gastrectomy. In samples from each carcinoma, gastrin peptides were characterized, using a library of sequence-specific immunoassays. Expression was also demonstrated by immunohistochemistry. In addition, the gastrin and gastrin/CCK-B receptor gene expression was quantitated using real-time PCR, and the receptor protein demonstrated by western blotting.
RESULTS: α-Amidated gastrins were detectable in 16 of 20 carcinomas (median concentration 2.1 pmol/g tissue; range 0-386 pmol/g tissue). The tissue concentrations correlated closely to the gastrin mRNA contents (r = 0.75, p < 0.0001). Moreover, progastrin and non-amidated processing intermediates, including glycine-extended gastrins, were detected in 19 carcinomas. Immunohistochemistry corroborated gastrin expression in carcinoma cells. Chromatography revealed extensive progastrin processing with α-amidated gastrin-34 and -17 (tyrosyl-sulfated as well as non-sulfated) as major products. Finally, gastrin/CCK-B receptor mRNA and protein were detected in all tumors.
CONCLUSIONS: The results show that the elements for a local loop of α-amidated gastrins and their receptor are detectable in 80% of human gastric adenocarcinomas. Therefore, the results support the contention that locally expressed gastrin may be involved in the tumorigenesis of gastric adenocarcinomas.

Song J, Ren H, Li Y, et al.
rG17PE38, a novel immunotoxin target to gastric cancer with overexpressed CCK-2R.
J Drug Target. 2013; 21(4):375-82 [PubMed] Related Publications
BACKGROUND: Gastrin/cholecystokinin subtype 2 receptor (CCK2R) is overexpressed in several types of tumors. Gastrin-17 (G17) peptide has a high affinity with CCK2R. These characters suggest that G17 may be useful for target cancer therapy.
PURPOSE: Construct a new immunotoxin (IT) targeting of CCK2R overexpressed gastric cancer.
METHODS: Two ITs were generated using forward and reverse G17 peptides fused with PE38. To get a high yield, codon optimized gene and optimized fermentation parameters were used in large-scale protein expression. An immunoaffinity technique was introduced into pseudomonas exotoxin (PE)-derived IT purification procedure. G17 competition, GST pull-down and indirect immunoflourescence assays were carried out to confirm the interaction between rG17 and CCK2R. Then, several cytotoxic assays were carried out on 18 cell lines, and an in vivo antitumor activity experiment was tested in nude mice.
RESULTS: The rG17PE38 showed specific cytotoxicity on three gastric cancer cells, while G17PE38 did not. After optimization, the expression level reached about 40% in medium deprived of NaCl. Next, 15-27.5 mg of pure rG17PE38 per 1 L of cultures was obtained. Results of G17 competition, GST pull-down and indirect immunoflourescence assays demonstrated that rG17 have a specific interact with CCK2R. Purified rG17PE38 showed high cytotoxicity on gastric cancer cell lines with the IC50 value of 0.6-4 ng·mL(-1). Treatment of nude mice inoculated with BGC-823 tumor xenografts with rG17PE38 efficiently inhibited tumor size.
CONCLUSIONS AND DISCUSSION: The present study demonstrates that reversed G17 could be used as target moiety of PE-derived IT and the rG17PE38 could be developed as a new immunotherapy agent. Codon optimized gene could increase the rG17PE38 expression level in E. coli and furthermore NaCl inhibits the rG17PE38 expression in large scale. Meanwhile, our present study inducts an immunoaffinity method in the IT purification procedure, which could purify the PE-derived ITs in native form.

Dockray GJ, Moore A, Varro A, Pritchard DM
Gastrin receptor pharmacology.
Curr Gastroenterol Rep. 2012; 14(6):453-9 [PubMed] Related Publications
C-terminally amidated gastrins act at cholecystokinin-2 receptors (CCK2R), which are normally expressed by gastric parietal and enterochromaffin-like (ECL) cells and smooth muscle; there is also extensive expression in the CNS where the main endogenous ligand is cholecystokinin. A variety of neoplasms express CCK2R, or splice variants, including neuroendocrine, pancreatic, medullary thyroid and lung cancers. Other products of the gastrin gene (progastrin, the Gly-gastrins) may stimulate cell proliferation but are not CCK2R ligands. Depending on the cell type, stimulation of CCK2R evokes secretion, increases proliferation and cell migration, inhibits apoptosis, and controls the expression of various genes. These effects are mediated by increased intracellular calcium and activation of protein kinase C, MAPkinase and other protein kinase cascades. There has been recent progress in developing CCK2R ligands that can be used for imaging tumours expressing the receptor. New antagonists have also been developed, and there is scope for using these for suppression of gastric acid and for treatment of neuroendocrine and other CCK2R-expressing tumours.

Quattrone A, Dewaele B, Wozniak A, et al.
Promoting role of cholecystokinin 2 receptor (CCK2R) in gastrointestinal stromal tumour pathogenesis.
J Pathol. 2012; 228(4):565-74 [PubMed] Related Publications
The cholecystokinin 2 receptor (CCK2R/CCKBR) is expressed in gastrointestinal stromal tumours (GISTs). We sought to investigate the role of CCK2R in GIST pathogenesis. Molecular characterization of CCK2R was performed on a heterogeneous cohort of 50 GISTs. In addition, CCK2R expression was evaluated by immunohistochemistry (IHC), using tissue microarray (TMA) containing 292 GISTs, two cases of hyperplasia of interstitial Cajal's cells (ICC) and six gastric microscopic GISTs. Mono-allelic loss of the CCK2R/11p15 allele was identified in 13.7% of GISTs, having no impact on the level of CCK2R transcript expression. No CCK2R mutations were found. The CCK2Ri4sv, CCK2R splice variant with retention of intron 4 was detected in six of 20 tumours analysed. Wild-type CCK2R transcripts were commonly expressed (57.1% of cases) and this expression was highly correlated with gastric primary site of GISTs (p < 0.001). At the protein level, expression of CCK2R in incidental ICC hyperplasia and early stages of gastric GIST development was documented, and its gastric association was confirmed on GIST-TMA by IHC. To explore the in vivo effect of CCK2R activation on tumour growth, gastrin versus placebo was administered intraperitoneally in nude mice carrying human GIST xenografts. The tumour volume was followed for 10 weeks. The effect of this stimulation on tumour cell proliferation/apoptosis was assessed by IHC and KIT/PKC-θ signalling was evaluated by western blotting (WB). In vivo experiments showed a two-fold increase in the volume of tumours which were exposed to gastrin in comparison with non-exposed controls (p = 0.03), with a significant increase in mitotic activity (p = 0.04) and Ki-67 proliferation index (p = 0.008). By WB, gastrin stimulation resulted in hyper-activation of KIT and PKC-θ kinases, and in evident PI3K-AKT pathway over-activation. Our results indicate a promoting role of CCK2R on GIST tumourigenesis, particularly in tumours of gastric origin.

Fino KK, Matters GL, McGovern CO, et al.
Downregulation of the CCK-B receptor in pancreatic cancer cells blocks proliferation and promotes apoptosis.
Am J Physiol Gastrointest Liver Physiol. 2012; 302(11):G1244-52 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Gastrin stimulates the growth of pancreatic cancer cells through the activation of the cholecystokinin-B receptor (CCK-BR), which has been found to be overexpressed in pancreatic cancer. In this study, we proposed that the CCK-BR drives growth of pancreatic cancer; hence, interruption of CCK-BR activity could potentially be an ideal target for cancer therapeutics. The effect of CCK-BR downregulation in the human pancreatic adenocarcinoma cells was examined by utilizing specific CCK-BR-targeted RNA interference reagents. The CCK-BR receptor expression was both transiently and stably downregulated by transfection with selective CCK-BR small-interfering RNA or short-hairpin RNA, respectively, and the effects on cell growth and apoptosis were assessed. CCK-BR downregulation resulted in reduced cancer cell proliferation, decreased DNA synthesis, and cell cycle arrest as demonstrated by an inhibition of G(1) to S phase progression. Furthermore, CCK-BR downregulation increased caspase-3 activity, TUNEL-positive cells, and decreased X-linked inhibitor of apoptosis protein expression, suggesting apoptotic activity. Pancreatic cancer cell mobility was decreased when the CCK-BR was downregulated, as assessed by a migration assay. These results show the importance of the CCK-BR in regulation of growth and apoptosis in pancreatic cancer. Strategies to decrease the CCK-BR expression and activity may be beneficial for the development of new methods to improve the treatment for patients with pancreatic cancer.

Smith JP, Harms JF, Matters GL, et al.
A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer.
Cancer Biol Ther. 2012; 13(3):164-74 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
There currently are no tests available for early diagnosis or for the identification of patients at risk for development of pancreatic cancer. We report the discovery of single nucleotide polymorphism (SNP) in the cholecystokinin B receptor (CCKBR) gene predicts survival and risk of pancreatic cancer. Growth of human pancreatic cancer is stimulated by gastrin through the CCKBR and an alternatively spliced isoform of the CCKBR gene called CCKCR. One hundred and ten surgically resected benign and malignant pancreatic tissues as well as normal pancreas were prospectively evaluated for CCKBR genotype and protein expression. Analysis demonstrated the expression of the spliced isoform, CCKCR, was associated with a (SNP) (C > A) at position 32 of the intron 4 (IVS 4) of the CCKBR gene. Since the SNP is within an intron, it has not previously been identified in the GWAS studies. Only patients with the A/A or A/C genotypes, exhibited immunoreactivity to a selective CCKCR antibody. Survival among pancreatic cancer patients with the A-SNP was significantly shorter (p = 0.0001, hazard ratio = 3.63) compared with individuals with C/C genotype. Other variables such as surgical margins, lymph node status, histologic grade or adjuvant chemotherapy were not associated with survival. Furthermore, having one or two of the A-alleles was found to increase the risk of pancreatic adenocarcinoma by 174% (p = 0.0192) compared with the C/C wild type. Cancer cells transfected to overexpress the CCKCR demonstrated increased proliferation over controls. Genetic screening for this SNP may aid in early detection of pancreatic cancer in high risk subjects.

Cayrol C, Bertrand C, Kowalski-Chauvel A, et al.
αv integrin: a new gastrin target in human pancreatic cancer cells.
World J Gastroenterol. 2011; 17(40):4488-95 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
AIM: To analyse αv integrin expression induced by gastrin in pancreatic cancer models.
METHODS: αv integrin mRNA expression in human pancreatic cancer cells was analysed using a "cancer genes" array and confirmed by real-time reverse transcription-polymerase chain reaction (PCR). Western blotting and semi-quantitative immunohistochemistry were used to examine protein levels in human pancreatic cancer cell lines and pancreatic tissues, respectively. The role of αv integrin on gastrin-induced cell adhesion was examined using blocking anti-αv integrin monoclonal antibodies. Adherent cells were quantified by staining with crystal violet.
RESULTS: Using a "cancer genes" array we identified αv integrin as a new gastrin target gene in human pancreatic cancer cells. A quantitative real-time PCR approach was used to confirm αv integrin gene expression. We also demonstrate that Src family kinases and the PI 3-kinase, two signalling pathways specifically activated by the CCK-2 receptor (CCK2R), are involved in gastrin-mediated αv integrin expression. In contrast, inhibition of the ERK pathway was without any effect on αv integrin expression induced by gastrin. Our results also show that gastrin modulates cell adhesion via αv integrins. Indeed, in vitro adhesion assays performed on fibronectin show that gastrin significantly increases adhesion of pancreatic cancer cells. The use of blocking anti-αv integrin monoclonal antibodies completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we showed in vivo that the targeted CCK2R expression in the pancreas of Elas-CCK2 mice, leads to the overexpression of αv integrin. This process may contribute to pancreatic tumour development observed in these transgenic animals.
CONCLUSION: αv integrin is a new gastrin target in pancreatic cancer models and contributes to gastrin effects on cell adhesion.

Song Y, Xu Y, Wang Z, et al.
MicroRNA-148b suppresses cell growth by targeting cholecystokinin-2 receptor in colorectal cancer.
Int J Cancer. 2012; 131(5):1042-51 [PubMed] Related Publications
MicroRNAs (miRNAs) play an important role in the regulation of a variety of cellular processes, including cell growth, differentiation, apoptosis and carcinogenesis. The purpose of this study was to elucidate the molecular mechanisms by which miR-148b acts as a tumor suppressor in colorectal cancer. The expression of miR-148b was significantly downregulated in 96 pairs of human colorectal cancer tissues (p<0.0001) and three cell lines (p<0.01) compared with non-tumor adjacent tissues by quantitative real-time PCR. The results of in situ hybridization highlighted that miR-148b was important in the cancer transformation process. Using statistical analysis, we found that the expression level of miR-148b was associated with tumor size (p=0.033) in colorectal cancer patients. Moreover, overexpression of miR-148b in HCT-116 and HT-29 cells could inhibit cell proliferation in vitro and suppress tumorigenicity in vivo. Importantly, the result of luciferase activity assay and western blot showed that the cholecystokinin-2 receptor gene (CCK2R) was a target of miR-148b and was downregulated by miR-148b at the translational level. Then, we used siRNA, radioimmunoassay and ELISA to demonstrate that miR-148b might have an effect on cell proliferation by regulating the expression of CCK2R which functioned depending on the gastrin in colorectal cancer. Taken together, our data provides the first evidences that miR-148b acts as a tumor suppressor in colorectal cancer and should be further evaluated as a biomarker and therapeutic tool against colorectal cancer.

Song YX, Yue ZY, Wang ZN, et al.
MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation.
Mol Cancer. 2011; 10:1 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
BACKGROUND: MicroRNAs (miRNAs) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Our previous studies have revealed that miR-148a and miR-152 are significantly down-regulated in gastrointestinal cancers. Interestingly, miR-148b has the same "seed sequences" as miR-148a and miR-152. Although aberrant expression of miR-148b has been observed in several types of cancer, its pathophysiologic role and relevance to tumorigenesis are still largely unknown. The purpose of this study was to elucidate the molecular mechanisms by which miR-148b acts as a tumor suppressor in gastric cancer.
RESULTS: We showed significant down-regulation of miR-148b in 106 gastric cancer tissues and four gastric cancer cell lines, compared with their non-tumor counterparts by real-time RT-PCR. In situ hybridization of ten cases confirmed an overt decrease in the level of miR-148b in gastric cancer tissues. Moreover, the expression of miR-148b was demonstrated to be associated with tumor size (P = 0.027) by a Mann-Whitney U test. We also found that miR-148b could inhibit cell proliferation in vitro by MTT assay, growth curves and an anchorage-independent growth assay in MGC-803, SGC-7901, BGC-823 and AGS cells. An experiment in nude mice revealed that miR-148b could suppress tumorigenicity in vivo. Using a luciferase activity assay and western blot, CCKBR was identified as a target of miR-148b in cells. Moreover, an obvious inverse correlation was observed between the expression of CCKBR protein and miR-148b in 49 pairs of tissues (P = 0.002, Spearman's correlation).
CONCLUSIONS: These findings provide important evidence that miR-148b targets CCKBR and is significant in suppressing gastric cancer cell growth. Maybe miR-148b would become a potential biomarker and therapeutic target against gastric cancer.

Muiños-Gimeno M, Espinosa-Parrilla Y, Guidi M, et al.
Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways.
Biol Psychiatry. 2011; 69(6):526-33 [PubMed] Related Publications
BACKGROUND: The involvement of microRNAs (miRNAs) in neuronal differentiation and synaptic plasticity suggests a role for miRNAs in psychiatric disorders; association analyses and functional approaches were used to evaluate the implication of miRNAs in the susceptibility for panic disorder.
METHODS: Case-control studies for 712 single-nucleotide polymorphisms (SNPs) tagging 325 human miRNA regions were performed in 203 Spanish patients with panic disorder and 341 control subjects. A sample of 321 anxiety patients and 642 control subjects from Finland and 102 panic disorder patients and 829 control subjects from Estonia was used as a replica. Reporter-gene assays and miRNA overexpression experiments in neuroblastoma cells were used to functionally evaluate the spectrum of genes regulated by the associated miRNAs.
RESULTS: Two SNPs associated with panic disorder: rs6502892 tagging miR-22 (p < .0002), and rs11763020 tagging miR-339 (p < .00008). Other SNPs tagging miR-138-2, miR-488, miR-491, and miR-148a regions associated with different panic disorder phenotypes. Replication in the north-European sample supported several of these associations, although they did not pass correction for multiple testing. Functional studies revealed that miR-138-2, miR-148a, and miR-488 repress (30%-60%) several candidate genes for panic disorder--GABRA6, CCKBR and POMC, respectively--and that miR-22 regulates four other candidate genes: BDNF, HTR2C, MAOA, and RGS2. Transcriptome analysis of neuroblastoma cells transfected with miR-22 and miR-488 showed altered expression of a subset of predicted target genes for these miRNAs and of genes that might be affecting physiological pathways related to anxiety.
CONCLUSIONS: This work represents the first report of a possible implication of miRNAs in the etiology of panic disorder.

Ellrichmann M, Ritter PR, Schrader H, et al.
Gastrin stimulates the VEGF-A promotor in a human colon cancer cell line.
Regul Pept. 2010; 165(2-3):146-50 [PubMed] Related Publications
INTRODUCTION: Hypergastrinemia has been observed in patients suffering from colorectal cancer. Vascular endothelial growth factor (VEGF) is known to play a pivotal role in tumour growth. Therefore, we addressed whether gastrin-17-gly and gastrin-17-amide regulate VEGF-A-gene and protein expression.
MATERIALS AND METHODS: Colo-320-cells were stably transfected with a VEGF-Luciferase-reporter gene. Luciferase activity was assessed after stimulation with various gastrin concentrations. Relevant promotor elements were identified by deletion analyses. VEGF protein levels in culture supernatants were quantified by ELISA.
RESULTS: VEGF-A stimulation with gastrin induced a dose- and time-dependent stimulation of luciferase activity. The greatest activities were found 6h after stimulation at concentrations of 10(-)(6)mmol/l. VEGF-promotor expression resulted in significantly (p<0.05) increased VEGF-A protein secretion. These effects were restricted to gastrin-17-amide.
CONCLUSION: Gastrin-17-amide enhances VEGF-A gene and protein expression in Colo320 cells stably transfected with a wild-type CCK-B/gastrin receptor. The induction of VEGF-A transcription and translation may contribute to the carcinogenic effects of gastrin observed in clinical studies. Therefore, CCK-B receptor antagonists may represent a treatment strategy in patients with colorectal cancer.

Jin G, Ramanathan V, Quante M, et al.
Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice.
J Clin Invest. 2009; 119(9):2691-701 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
Hyperproliferation of the colonic epithelium, leading to expansion of colonic crypt progenitors, is a recognized risk factor for colorectal cancer. Overexpression of progastrin, a nonamidated and incompletely processed product of the gastrin gene, has been shown to induce colonic hyperproliferation and promote colorectal cancer in mice, but the mechanism of pathogenesis has not been defined. Cholecystokinin-2 receptor (CCK2R) is the primary receptor for cholecystokinin (CCK) and amidated gastrin. Here, we show that Cck2r was expressed in murine colonic crypts and upregulated in the transgenic mice that overexpress human progastrin. Murine deletion of Cck2r abrogated progastrin-dependent increases in colonic proliferation, mucosal thickness, and beta-catenin and CD44 expression in the colon tumor. In addition, either deletion or antagonism of Cck2r resulted in the inhibition of progastrin-dependent increases in progenitors expressing doublecortin and CaM kinase-like-1 (DCAMKL1), stem cells expressing leucine rich repeat-containing G protein-coupled receptor 5 (LgR5), and colonic crypt fission. Furthermore, in the azoxymethane mouse model of colorectal carcinogenesis, Cck2r deletion in human progastrin-overexpressing mice resulted in markedly decreased aberrant crypt foci formation and substantially reduced tumor size and multiplicity. Taken together, these observations indicate that progastrin induces proliferative effects, primarily in colonic progenitor cells, through a CCK2R-dependent pathway. Moreover, our data suggest that CCK2R may be a potential target in the treatment or prevention of colorectal cancer.

Oikonomou E, Buchfelder M, Adams EF
Cholecystokinin (CCK) and CCK receptor expression by human gliomas: Evidence for an autocrine/paracrine stimulatory loop.
Neuropeptides. 2008; 42(3):255-65 [PubMed] Related Publications
Cholecystokinin (CCK) is a gut-brain peptide has been described to be able to induce mitosis according to recent studies. Additionally, conflicting data has been published on whether tumours of the central and peripheral nervous system in general, and gliomas in particular, express CCK receptors. In the present in vitro study we employed reverse transcription followed by the polymerase chain reaction (RT-PCR) to investigate whether mRNA for CCK-A and CCK-B receptors as well as CCK peptide itself is present in primary human gliomas and the U-87 MG GBM cell line. The data show that 14/14 (100%) of the primary gliomas exhibited mRNA expression for the CCK peptide gene and the B receptor including the U-87 MG cells, whereas, only 2/14 (14%) showed presence of the CCK-A receptor. The presence of CCK receptors together with CCK peptide expression itself suggests presence of an autocrine loop controlling glioma cell growth. In support of this conclusion, a neutralizing antibody against the CCK peptide exhibited a dose dependent inhibition of cell growth whereas, antagonists to CCK caused a dose depend inhibition of exogenous stimulated glioma cell growth in vitro, via the CCK-B receptor which is PKC activated. Assessment of apoptosis and proteasome activity were undertaken and we report that treatment with CCK antagonists decreased proteasome and increased caspase-3 activity. These data indicate that CCK peptide and CCK-B are abundant in human gliomas and they act to stimulate cell growth in an autocrine manner, primarily via the high affinity CCK-B receptor, which was blocked by antagonists to CCK, perhaps via apoptosis.

Oikonomou E, Charlton A, Buchfelder M, Adams EF
Cholecystokinin (CCK) receptor and CCK gene expression in human pituitary adenomas and in vitro effects of CCK peptides on GH and gonadotrophin secretion.
Exp Clin Endocrinol Diabetes. 2007; 115(10):683-9 [PubMed] Related Publications
There is growing evidence that cholecystokinin (CCK) affects growth and differentiation of anterior pituitary cells, via the CCK-B receptor. The possibility of an autocrine / paracrine role for CCK to modulate hormone secretion in human pituitary tumour cells is demonstrated here by RT-PCR and direct sequencing. In support of this conclusion, a neutralising antibody against the CCK peptide exhibited a dose dependent inhibition of hormone secretion by functionless pituitary adenomas. Total RNA was extracted from human pituitary adenomas, reverse transcribed into cDNA and subjected to PCR using primers specific for the gene for CCK, CCK-A and CCK-B receptors. PCR bands of the predicted length were observed in all tumours using human CCK gene and CCK-B receptor primers. Restriction digestion and direct sequence analysis provided further evidence that they represented both the human CCK peptide along with the CCK-A and/B receptor mRNA. CCK-33 and CCK octapeptide sulphate (CCK-8s) both powerfully stimulated phosphatidylinositol hydrolysis, providing evidence for functional activity of the CCK-A and/B receptors. A direct stimulatory effect of CCK peptides on both LH and FSH secretion is reported for the first time, whereas stimulatory effects on GH were blocked by antagonists to CCK. These results may indicate an autocrine role for CCK in the functioning and perhaps development of human pituitary tumours.

Cramer T, Jüttner S, Plath T, et al.
Gastrin transactivates the chromogranin A gene through MEK-1/ERK- and PKC-dependent phosphorylation of Sp1 and CREB.
Cell Signal. 2008; 20(1):60-72 [PubMed] Related Publications
Our previous work revealed that gastrin regulates chromogranin A (CgA) transcription through enhanced binding of Sp1, CREB and Egr-1 to a proximal gastrin-responsive promoter element (Gas-RE). Here, we provide a detailed characterization of the signalling pathways transmitting the effect of gastrin on the CgA promoter. Gastrin treatment of gastric AGS-B cells potently stimulated MEK-1 as well as MAP kinases ERK-1/-2, JNK and p38 in a time-dependent manner. Interruption of ERK-1/-2/MEK-1 pathways abolished the transactivating effect of gastrin, whereas blockade of JNK or p38 activity was without effect. Functional promoter analysis revealed that the minimal element CgA-85/-64 was sufficient and necessary to confer MEK-1/ERK responsiveness. Analysis of proximal signalling pathways showed that activation of the MEK-1/ERK-1/2 module by gastrin does not require Ras, PI3-kinase or intracellular calcium signals, but depends on activation of kinases of the PKC family. This report demonstrates that a pathway comprising PKCs>Raf-1>MEK-1>ERK-1/-2 mediates the effect of gastrin on the CgA promoter, and strongly suggests that enhanced phosphorylation of Sp1 and CREB is crucial for CgA transactivation through the G protein-coupled CCK-B/gastrin receptor.

Yu HG, Tong SL, Ding YM, et al.
Enhanced expression of cholecystokinin-2 receptor promotes the progression of colon cancer through activation of focal adhesion kinase.
Int J Cancer. 2006; 119(12):2724-32 [PubMed] Related Publications
Focal adhesion kinase (FAK) is suggested to be intimately involved in the progression of malignancies. Our previous research has demonstrated that activation of cholecystokinin-2 receptor (CCK2R) by gastrin stimulates a rapid activation of FAK pathway in human colon cancer cells. The purpose of this study is to determine the role of CCK2R and FAK in the progression of colon cancer. In this study, matched tissue samples of primary colon cancer and adjacent normal colon mucosa from the same patient were collected from 45 patients with colon cancer undergoing surgical resection. The gastrin expression was detected using reverse transcription polymerase chain reaction (RT-PCR). The CCK2R expression was examined by in situ hybridization and RT-PCR. The expression of FAK and phosphorylated FAK at tyrosine 397 (phospho-FAK) were detected using immunohistochemistry and immunoblotting. Colo320 and SW787, 2 colon cancer cell lines with or without CCK2R expression, were recruited in this study. Antisense oligonucleotide of FAK was used to block the expression of FAK. Invasiveness and motility of colon cancer cells were detected by Boyden chamber. In this series, enhanced expression of gastrin, CCK2R, FAK and phospho-FAK were observed in colon cancer tissues. CCK2R expression correlated with expression of phospho-FAK. Coexpression of CCK2R and phospho-FAK associated with invasion and lymph node metastasis. Increased invasion and motility was induced by gastrin in Colo320 cells. Overexpression of CCK2R by stable transfection of CCK2R plasmid amplified this increase and incubation with 1 microM L-365,260, a specific CCK2R antagonist, completely inhibited the effect of gastrin. FAK antisense largely blocked the increase of invasion and motility in Colo320 cells. Our data represent the evidence for the CCK2R regulating invasion and motility of colon cancer cells, and support a role of CCK2R in the progression of colon cancer. FAK play a critical role in this CCK2R-mediated effect.

Cayrol C, Clerc P, Bertrand C, et al.
Cholecystokinin-2 receptor modulates cell adhesion through beta 1-integrin in human pancreatic cancer cells.
Oncogene. 2006; 25(32):4421-8 [PubMed] Related Publications
Several lines of evidence suggest that gastrin and the CCK-2 receptor (CCK2R) could contribute to pancreatic carcinogenesis by modulating processes such as proliferation, cell adhesion or migration. In the current study, we used a 'cancer gene array' and identified beta1-integrin subunit as a new gastrin-regulated gene in human pancreatic cancer cells. We also demonstrated that Src family kinases and the phosphatidylinositol-3-kinase (PI-3-kinase) pathway play a crucial role in the expression of beta1-integrin induced by gastrin. Our results also showed that gastrin modulates cell-substrate adhesion via beta1-integrin. Indeed, using blocking anti-beta1-integrin monoclonal antibodies, we completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we observed that in response to gastrin, beta1-integrin is tyrosine phosphorylated by Src family kinases and associates with paxillin, a scaffold protein involved in focal adhesion and integrin signalling. This mechanism might be involved in gastrin-induced cell adhesion. Moreover, we showed in vivo that targeted CCK2R expression in the pancreas of Elas-CCK2 mice leads to the overexpression of beta1-integrin. This process may contribute to pancreatic tumour development observed in these transgenic animals.

Mathieu V, Mijatovic T, van Damme M, Kiss R
Gastrin exerts pleiotropic effects on human melanoma cell biology.
Neoplasia. 2005; 7(10):930-43 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
The effects of gastrin (G17) on the growth and migration factors of four human melanoma cell lines (HT-144, C32, G-361, and SKMEL-28) were investigated. The expression patterns of cholecystokinin (CCK)(A), CCK(B), and CCK(C) gastrin receptors were investigated in these cells and in seven clinical samples by means of reverse transcription polymerase chain reaction. Melanoma cells appear to express mRNA for CCK(C) receptors, but not for CCK(A) or CCK(B) receptors. Although gastrin does not significantly modify the growth characteristics of the cell lines under study, it significantly modifies their cell migration characteristics. These modifications occur at adhesion level by modifying the expression levels of alpha(v) and beta3 integrins, at motility level by modifying the organization of the actin cytoskeleton, and at invasion level by modifying the expression levels of matrix metalloproteinase 14. We recently demonstrated the presence of CCK(B) receptors in mouse endothelial cells involved in glioblastoma neoangiogenesis. Chronic in vivo administration of a selective CCK(B) receptor antagonist to mice bearing xenografts of human C32 melanoma cells significantly decreased levels of neoangiogenesis, resulting in considerable delays in the growth of these C32 xenografts. In conclusion, our study identifies the pleiotropic effects of gastrin on melanoma cell biology.

Yu HG, Schäfer H, Mergler S, et al.
Valine-286 residue in the third intracellular loop of the cholecystokinin 2 receptor exerts a pivotal role in cholecystokinin 2 receptor mediated intracellular signal transduction in human colon cancer cells.
Cell Signal. 2005; 17(12):1505-15 [PubMed] Related Publications
Although expression of the gastrin/cholecystokinin-2 receptor (CCK2R) is widely reported in human colorectal cancer, little is known on its role in mediating mature amidated gastrin (gastrin-17 amide, G-17) induced intracellular signal transduction in colon cancer cells. The purpose of this study was to explore the intracellular events of colorectal cancer cells after gastrin binding to CCK2R. Meanwhile, the influence of a natural point mutation 286V-->F in the third intracellular loop of CCK2R on gastrin-envoked intracellular signal transduction was also investigated. Firstly, Colo320 cells were stably transfected with wild type (Colo320 WT) and mutant CCK2R (Colo320 M), respectively. The intracellular signal transduction events in response to gastrin were investigated in both Colo320 WT and Colo320 M cells. In Colo320 WT cells, G-17 induced formation of intracellular cyclic AMP and inositol 1,4,5-trisphosphate, and stimulated intracellular calcium mobilization. G-17 also stimulated tyrosine phosphorylation of ERKl/2, p38, FAK, and paxillin, and up-regulated the mRNA expression of early response gene c-Jun and c-Fos. However, G-17 inhibited proliferation and induced apoptosis in Colo320 WT cells. Mutation 286V-->F in the third intracellular loop of CCK2R blocked G-17 induced biological without affecting binding affinity of CCK2R to G-17. Our results suggest that activation of CCK2R by gastrin stimulates heterotrimeric G-protein Gq and G(12/13) mediated intracellular signal transduction pathway in colon cancer cells. The valine-287 residue in third intracellular loop of CCK2R plays a pivotal role in CCK2R mediated intracellular signal transduction.

Zhou JJ, Chen ML, Zhang QZ, et al.
Coexpression of cholecystokinin-B/gastrin receptor and gastrin gene in human gastric tissues and gastric cancer cell line.
World J Gastroenterol. 2004; 10(6):791-4 [PubMed] Article available free on PMC after 01/05/2017 Related Publications
AIM: To compare the expression patterns of cholecystokinin-B (CCK-B)/gastrin receptor genes in matched human gastric carcinoma and adjacent non-neoplastic mucosa of patients with gastric cancer, inflammatory gastric mucosa from patients with gastritis, normal stomachs from 2 autopsied patients and a gastric carcinoma cell line (SGC-7901), and to explore their relationship with progression to malignancy of human gastric carcinomas.
METHODS: RT-PCR and sequencing were employed to detect the mRNA expression levels of CCK-B receptor and gastrin gene in specimens from 30 patients with gastric carcinoma and healthy bordering non-cancerous mucosa, 10 gastritis patients and normal stomachs from 2 autopsied patients as well as SGC-7901. The results were semi-quantified by normalizing it to the mRNA level of beta-actin gene using Lab Image software. The sequences were analyzed by BLAST program.
RESULTS: CCK-B receptor transcripts were detected in all of human gastric tissues in this study, including normal, inflammatory and malignant tissues and SGC-7901. However, the expression levels of CCK-B receptor in normal gastric tissues were higher than those in other groups (P<0.05), and its expressions did not correlate with the differentiation and metastasis of gastric cancer (P>0.05). On the other hand, gastrin mRNA was detected in SGC-7901 and in specimens obtained from gastric cancer patients (22/30) but not in other gastric tissues, and its expression was highly correlated with the metastases of gastric cancer (P<0.05).
CONCLUSION: Human gastric carcinomas and gastric cancer cell line SGC-7901 cells coexpress CCK-B receptor and gastrin mRNA. Gastrin/CCK-B receptor autocrine or paracrine pathway may possibly play an important role in the progression of gastric cancer.

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