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[Cancer Research 64, 1915-1919, March 15, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

An Antiapoptotic Role for Gastrin and the Gastrin/CCK-2 Receptor in Barrett’s Esophagus

Joseph C. Harris1, Philip A. Clarke1, Altaf Awan1, Janusz Jankowski2 and Susan A. Watson1

1 Academic Unit of Cancer Studies, University of Nottingham, Nottingham, and 2 Department of Cancer Biomarkers, University of Leicester, Leicester, United Kingdom


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Mechanisms by which premalignant Barrett’s metaplasia (BM) progresses to esophageal adenocarcinoma are currently being sought. This study investigated the role played by the polypeptide hormone gastrin, specifically its antiapoptotic effects through activation of protein kinase B/Akt (PKB/Akt). In esophageal cell lines with low basal levels of activated PKB/Akt, phosphorylation could be induced by exogenous amidated gastrin. High basal levels of activated PKB/Akt were linked to endogenous gastrin expression and were reduced by treatment with a cholecystokinin-type 2 receptor (CCK-2R) antagonist. Expression of a constitutively active splice variant of the CCK-2R additionally increased basal activation of PKB/Akt. It is proposed that gastrin acting in an autocrine and endocrine manner via a CCK-2R isoform may activate PKB/Akt and that with expression of gastrin and CCK-2R isoforms increasing in BM samples, gastrin may aid progression of BM through amplification of antiapoptotic pathways. Evidence for this proposal was provided through the observed specific up-regulation of PKB/Akt in BM samples.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Barrett’s esophagus (BE) is a premalignant condition of the lower esophagus caused by prolonged gastroesophageal reflux and characterized by a metaplastic change from normal squamous to columnar intestinal-type epithelium (1) . The prevalence of Barrett’s metaplasia in the population is estimated to be between 5 and 9% and is associated with an increased risk of progression to esophageal adenocarcinoma (2) . This study aimed to investigate a link between gastrin and antiapoptotic mechanisms in the metaplastic esophageal environment.

Gastrin has recently been shown to increase transcription of a number of target genes, such as ligands of the epidermal growth factor receptor (3) and cyclooxygenase 2 (4) , as well as exhibiting angiogenic (5) and antiapoptotic properties (6) . Up-regulated gastrin production through a number of scenarios, including use of proton pump inhibitors (7) , may therefore aid the progression of BE to esophageal adenocarcinoma. Gastrin acts via the cholecystokinin type-2 receptor (CCK-2R), a member of the 7-transmembrane domain G-protein-coupled receptor superfamily. A novel splice variant named CCK-2Ri4sv has recently been described, which exhibits constitutive activation (8) .

An important downstream effect of CCK-2R activation is the phosphorylation/activation of the potent antiapoptotic factor, protein kinase B (PKB)/Akt (6) . Once phosphorylated PKB/Akt can itself inactivate a range of proapoptotic factors, including caspase-9, Bad, and the forkhead/winged-helix transcription factors important in the transcription of the cell death ligand Fas, as well as activating the antiapoptotic inhibitor {kappa}B kinase cascade (9) . This study was aimed at determining the antiapoptotic potential of increased gastrin, CCK-2R, and CCK-2Ri4sv expression in human BE samples, using transfected human esophageal adenocarcinoma cell lines as in vitro models.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Human Tissue Sample Collection.
Endoscopic biopsy samples were collected by both Professor Janusz Jankowski (Leicester Royal Infirmary, Leicester, United Kingdom) and Altaf Awan (Derby Royal Infirmary, Derby, United Kingdom). Samples were made anonymous according to Medical Research Council good clinical research practice guidelines and were collected after local National Health Service Ethical Committee guidelines in both centers. They were analyzed by a pathologist and verified as being normal or Barrett’s metaplasia.

Cell Culture.
OE19 (esophageal adenocarcinoma pathological stage III), OE21 (esophageal squamous carcinoma pathological stage III), OE33 (Barrett’s metaplasia-derived esophageal adenocarcinoma pathological stage II), and AR42J (rat exocrine pancreatic) cells known to express the classical CCK-2R were cultured in RPMI 1640 (Sigma, Poole, United Kingdom) with the addition of 10% fetal bovine serum (Sigma). The cells were maintained in a humidified environment at 37°C and 5% CO2.

Transfection with the CCK-2Ri4sv.
OE33 cells were stably transfected with a pcDNA3.1 vector containing a CCK-2Ri4sv insert (obtained from Mark Hellmich; Department of Surgery, University of Texas, Galveston, TX) using the Promega Transfast Transfection Reagent (Promega, Madison, WI).

RNA Extraction and Reverse Transcription.
Total RNA was extracted from human biopsy and in vitro cell samples using RNA-Bee (Biogenesis; Poole, Dorset, United Kingdom) with reverse transcription being carried out using Superscript II reverse transcriptase reagents (Invitrogen, United Kingdom) as described previously (10) .

Real-Time PCR.
mRNA expression in cell lines and tissue samples was determined via real-time PCR, using fluorescent SYBR green dye to allow semiquantitative analysis of gene expression levels. Optimized primers designed to bind the gastrin, CCK-2R, and CCK-2Ri4sv genes were used in conjunction with reagents from the qPCR Core kit for SYBR Green I (Eurogentec, Romsey, United Kingdom). PCR assays were carried out on a 5700 Sequence Detection System (PE Biosystems, Warrington, United Kingdom).

Western Blotting.
The effect of 10-8 M exogenous gastrin stimulation on PKB/Akt phosphorylation was assessed via Western blotting using specific anti-PKB/Akt and anti-phospho-PKB/Akt antibodies (Cell Signaling Technologies, Beverly, MA). The manufacturer’s protocol was followed, with horseradish peroxidase labeled swine antirabbit secondary antibodies (Dako Cytomation, Ely, United Kingdom) being used at 1/1000. Target proteins were visualized after enhanced chemiluminescence treatment of membranes and subsequent exposure to X-OMAT X-ray film (Sigma). CCK-2R was detected in the OE lines using an anti-CCK-2R antibody (Aphton Corporation, Woodland, CA) raised against the first extracellular domain of the receptor (11) . The CCK-2R antagonist YM022 used at 10-8 M was kindly donated by the James Black Foundation (Dulwich, London, United Kingdom).

Immunohistochemical Evaluation of Gastrin and CCK-2R in OE Cells.
OE cells were cultured in 8-well SuperCell chamber slides (Menzel-Gläser, Braunschweig, Germany) for 24 h then fixed in 4% paraformaldehyde. Interspersed with PBS washes, the cells were incubated with either an anti-CCK-2R rabbit primary antibody (Aphton Corporation) followed by swine antirabbit FITC-labeled secondary (Dako Cytomation, Ely, United Kingdom) or with an anti-progastrin rabbit primary (Aphton Corporation) followed by Alexa Fluor 594-labeled goat antirabbit secondary (Molecular Probes, Eugene, OR). Necessary controls were also prepared. Slides were treated with Slow Fade Light Antifade Solution with 4',6-diamidino-2-phenylindole (Molecular Probes) before fluorescent microscopy analysis.

Immunohistochemical Evaluation of PKB/Akt and Phospho-PKB/Akt in Human Normal and Barrett’s Samples.
Immunohistochemical labeling using murine PKB/Akt and rabbit polyclonal phosphorylated PKB/Akt antibodies (both Cell Signaling Technology) was carried out on formalin-fixed, paraffin-embedded esophageal biopsy tissue (n = 8 for each sample type) by indirect streptavidin biotin-labeling technique (StreptABC system; DakoCytomation, Ely, United Kingdom) according to manufacturers instructions. Visualization was via diaminobenzidine tetra hydrochloride chromogen (Liquid DAB system; DakoCytomation). In the case of the murine PKB/Akt antibody, nonspecific cross-reactivity was controlled for using an irrelevant IgG1 monoclonal antibody at matched concentration. Nonspecific cross-reactivity for the polyclonal phosphorylated PKB/Akt antibody was controlled for by preabsorption with the Ser473 blocking peptide as per manufacturer’s instructions (Cell Signaling Technology). Staining intensity was assessed in 10 fields of view for each normal and Barrett’s sample using the QWin Standard image analysis system (Leica Microsystems, Cambridge, United Kingdom).


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Tissue Sample Analysis.
Paired human normal and Barrett’s metaplasia biopsy samples were analyzed via semiquantitative real-time PCR for relative expression levels of gastrin (n = 16), CCK-2R (n = 18), and CCK2Ri4sv (n = 32). mRNA levels for these key genes were expressed relative to levels of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase. Significant increases in gene expression (calculated via the Wilcoxon signed rank test) for all three genes were observed [gastrin, P = 0.0076, 29.2-fold increase (Fig. 1A)Citation ; CCK2R, P = 0.0068, 7.8-fold increase (Fig. 1B)Citation and there was de novo expression of CCK2Ri4sv; P = 0.0077 (Fig. 1C)Citation ] in the BE samples compared with their paired normals.



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  		Fig. 1. Gene expression of three genes in human Barrett’s versus normal biopsy samples via real-time PCR. A, gastrin. B, cholecystokinin-type 2 receptor (CCK-2R). C, CCK-2Ri4sv. Significant up-regulation of all three genes was observed in the premalignant Barrett’s samples compared with their paired normals as shown in the figures (Wilcoxon signed rank test). Samples in which expression could not be detected are shown as having relative expression levels of 0.00001.

 
Evaluation of CCK-2R and Gastrin Expression in Esophageal Cells.
CCK-2R protein expression was confirmed via immunohistochemical staining, with the presence of the receptor established in all three esophageal cell lines, predominantly at the plasma membrane. Fig. 2ACitation shows a representative staining pattern with OE19 cells. Western blot analysis using a specific CCK-2R antibody confirmed that the classical 74-kDa isoform of the receptor was expressed (Fig. 2B)Citation . There was no evidence of the intron 4 splice variant, which the NH2-terminal CCK-2R antiserum would have detected at a molecular weight of 82–85kDa, which was confirmed by gene expression studies (results not shown).



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  		Fig. 2. Expression of cholecystokinin-type 2 receptor (CCK-2R) and gastrin protein in three esophageal cell lines. A, using immunohistochemistry, OE cell lines were stained with a monoclonal anti-CCK-2R antibody, representative staining of the OE19 cell line is shown. The CCK-2R is localized at the plasma membrane and clustered at intracellular locations. B, Western blotting using an anti-CCK-2R antibody suggests that it is the classical isoform of the receptor, which is being expressed by all three esophageal cell lines. C, immunohistochemical staining of OE19 cells using an anti-progastrin antibody. Gastrin is observed at high levels in an intracellular perinuclear granular pattern.

 
Both immunohistochemical staining and real-time PCR analysis (results not shown) were used to confirm expression of gastrin in the esophageal cell lines. Fig. 2CCitation shows OE19 cells fluorescently labeled with anti-progastrin antibodies, with gastrin localization showing a perinuclear granular clustering pattern. Relative gastrin gene expression values were observed to be 0.65 for OE19 compared with 0.23 for the other adenocarcinoma line, OE33.

Effect of Exogenous Gastrin on PKB/AKT Phosphorylation in Esophageal Cells.
The effect of exogenous gastrin on PKB/Akt phosphorylation was examined after induction of apoptosis via 24-h serum withdrawal. Ten nM gastrin were added to the medium, and Western blot analysis was then performed using specific anti-PKB/Akt and anti-phospho-PKB/Akt antibodies. Serum-starved AR42J cells showed no PKB/Akt phosphorylation in the absence of gastrin but demonstrated an increase in phosphorylation after gastrin stimulation, an event that reached its maximal level at 30 min (Fig. 3A)Citation , as confirmed via densitometry. Similar results were obtained for the three esophageal lines. Maximal phosphorylation was observed at 30 min in the OE33 cells and 60 min in the OE21 cells and was observed to be at constitutively high levels in the OE19 cells (Fig. 3B)Citation .



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  		Fig. 3. Effect of amidated gastrin stimulation on the phosphorylation status of protein kinase B (PKB)/Akt. A, the positive control pancreatic cell line AR42J was incubated with amidated gastrin. Western blots were carried out on lysates from these cells to determine whether gastrin stimulation had any effect on PKB/Akt phosphorylation status. Specific antibodies raised against total PKB/Akt and phosphorylated PKB/Akt were used. B, effect of amidated gastrin on PKB/Akt phosphorylation in the three OE cell lines. C, effect of YM022 on basal PKB/Akt phosphorylation levels in the esophageal adenocarcinoma cell line OE19. Cells were incubated with the CCK-2R antagonist for varying time periods and then total and phosphorylated PKB/Akt levels assessed.

 
The Effect of YM022 Blockade of the CCK-2R on PKB/Akt Phosphorylation in OE19 Cells.
OE19 cells shown to exhibit constitutive PKB/Akt phosphorylation were serum starved and then treated with the CCK-2R antagonist YM022 at 10 nM. This treatment resulted in a reduction in the levels of basal Akt phosphorylation observed in the cell line. Phosphorylation was almost completely inhibited after a 60-min incubation period (Fig. 3C)Citation with no effect on cell viability.

Transfection of OE33 Cells with the CCK-2Ri4sv.
Chosen for having the lowest basal PKB/Akt phosphorylation after serum withdrawal, OE33 cells were stably transfected with the constitutively active isoform of the gastrin receptor CCK-2Ri4sv. Western blot analysis of these cells showed an increase in basal phosphorylation status of the antiapoptotic protein compared with that observed in the vector control transfected cells. Phosphorylation increased additionally after gastrin stimulation for 60 min (Fig. 4A)Citation . Phosphorylation of PKB/Akt in the CCK-2Ri4sv-transfected lines could be reduced after YMO22 treatment, indicating a role for the receptor in the process (Fig. 4B)Citation .



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  		Fig. 4. Comparison between effect of gastrin on PKB/Akt phosphorylation status in OE33vc and OE33 cholecystokinin-type 2 receptor (CCK-2R)i4sv cells, determined via Western blotting. A, increases in phosphorylation were seen as stimulation time increased for both cell lines, with the highest basal constitutive phosphorylation seen in the CCK-2Ri4sv-transfected line. B, blockading the CCK-2Ri4sv with YM022 resulted in a down-regulation in PKB/Akt phosphorylation confirming this receptor is involved in the antiapoptotic process.

 
Evaluation of PKB/Akt Phosphorylation Status in Normal and Barrett’s Samples.
Using immunohistochemical methods, paired normal and Barrett’s samples (n = 8) were assessed for levels of total and phosphorylated PKB/Akt using specific antibodies. Quantification of immunohistochemistry was carried out using image analysis software macro routines. A binary mask was used to highlight positive antibody staining on a digitized color picture of the tissue, the gray level intensity of each pixel measured, and the mean value found for 10 representative fields of view. Higher gray level intensities correspond to higher levels of antibody binding. These averages could hence be compared and the total mean for all samples calculated. Levels of total PKB/Akt staining were consistently intense in both normal and Barrett’s samples; however, a significant difference in phospho-PKB/Akt staining was observed (Paired Samples T Test, P < 0.008 for each pair). Negligible phospho-Akt levels (mean gray level intensity = 7.5) were present in all normal samples (Fig. 5A)Citation with high levels (mean gray level intensity = 59.9) observed in all metaplastic Barrett’s samples (Fig. 5B)Citation . With regard to the latter, staining was focused in the metaplastic intestinal crypts.



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  		Fig. 5. Comparison between protein kinase B (PKB)/Akt phosphorylation status in Barrett’s and normal tissue determined via immunohistochemical staining. A, normal esophageal squamous epithelium showing no phospho-PKB/Akt staining. B, Barrett’s metaplastic epithelium staining positive for phospho-PKB/Akt, and levels of total PKB/Akt were constant between the normal and Barrett’s tissue.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Amidated gastrin increases phosphorylation/activation of the antiapoptotic factor PKB/Akt in a time-dependent fashion in three esophageal cell lines. Additionally, compared with the AR42J control cell line, higher basal phosphorylation levels were observed in the esophageal cell lines, a phenomenon attributed to their relatively higher level of endogenous gastrin expression, which could act in an autocrine/juxtacrine fashion on the classical CCK-2R. Evidence supporting this theory was provided by blockading the CCK-2R of the esophageal adenocarcinoma cell line OE19, which resulted in a decrease in PKB/Akt phosphorylation. No exogenous gastrin was present in the cell growth media, and hence, it is concluded the basal Akt phosphorylation may partially result from autocrine gastrin stimulation. The three esophageal lines were chosen for their exclusive expression of the classical CCK-2R isoform to gain a clearer understanding of the functionality of the CCK-2Ri4sv after transfection into the cells.

A similar high level of constitutive PKB/Akt phosphorylation was observed in OE33 cells after transfection with the splice variant receptor CCK-2Ri4sv. This increase is attributed to the apparent constitutive signaling capability of the CCK-2Ri4sv that results in Ca2+ oscillation even in the absence of ligand binding (8) .

Previous research using human BE metaplastic samples has shown an increase in CCK-2R expression levels (12) compared with normal mucosa, with this current research additionally showing an increase in gastrin and CCK-2Ri4sv gene expression in the same sample type. These findings correlate with the observed significant increase in activated PKB/Akt seen in BE tissue compared with normal tissue. It is concluded that gastrin, in conjunction with CCK-2R isoforms, may reduce cell death in metaplastic BE through increased activation of PKB/Akt, thus aiding malignant progression.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Susan A. Watson, Academic Unit of Cancer Studies, D Floor, West Block, Queen’s Medical Centre, University Hospital, Nottingham, NG7 2UH, United Kingdom. Phone: 44-0-115-9709248; Fax: 44-0-115-9709902; E-mail: sue.watson{at}nottingham.ac.uk

Received 8/29/03. Revised 1/21/04. Accepted 1/23/04.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Jankowski JA, Harrison RF, Perry I, Balkwill F, Tselepis C. Barrett’s metaplasia. Lancet, 356: 2079-85, 2000.[CrossRef][Medline]
  2. Geobes K, Van Eyken P. The diagnosis of dysplasia and malignancy in Barrett’s oesophagus. Histopathology, 37(2): 99-107, 2000.
  3. Varro A, Noble PJ, Wroblewski LE, Bishop L, Dockray GJ. Gastrin-cholecystokinin(B) receptor expression in AGS cells is associated with direct inhibition and indirect stimulation of cell proliferation via paracrine activation of the epidermal growth factor receptor. Gut, 50(6): 827-33, 2002.
  4. Guo YS, Cheng JZ, Jin GF, Gutkind JS, Hellmich MR, Townsend CM, Jr. Gastrin stimulates cyclooxygenase-2 expression in intestinal epithelial cells through multiple signaling pathways. Evidence for involvement of ERK5 kinase and transactivation of the epidermal growth factor receptor. J Biol Chem, 277(50): 48755-63, 2002.
  5. Clarke PA, Evans S, McWilliams D, Watson SA. Angiogenic potential of HUVEC cells is increased by amidated and glycine-extended gastrin-17. Gastroenterology, 122(S1): S914 2002.
  6. Todisco A, Ramamoorthy S, Witham T, et al Molecular mechanisms for the antiapoptotic action of gastrin. Am J Physiol Gastrointest Liver Physiol, 280: G298-307, 2001.[Abstract/Free Full Text]
  7. Nemeth J, Varro A, Bridson J, Walker R, Dockray GJ. Increased tissue concentrations of the gastrin precursor in patients treated with omeprazole. Eur J Clin Investig, 22: 638-44, 1992.[Medline]
  8. Hellmich MR, Rui X-L, Hellmich HL, Fleming RYD, Evers BM, Townsend CM, Jr. Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth. J Biol Chem, 275(41): 32122-8, 2000.
  9. Cross TG, Scheel-Toellner D, Henriquez NV, Deacon E, Salmon M, Lord JM. Serine/threonine protein kinases and apoptosis. Exp Cell Res, 256(1): 34-41, 2000.
  10. McWilliams DF, Watson SA, Crosbee DM, Michaeli D, Seth T. Co-expression of gastrin and gastrin receptors (CCK-B and {Delta}CCK-B) in gastrointestinal tumour cell lines. Gut, 42: 795-8, 1998.[Abstract/Free Full Text]
  11. Watson SA, Clarke PA, Smith AM, et al Expression of CCKB/gastrin receptor isoforms in gastrointestinal tumour cells. Int J Cancer, 77: 572-7, 1998.[CrossRef][Medline]
  12. Haigh CR, Attwood SE, Thompson DG, et al Gastrin induces proliferation in Barrett’s metaplasia through activation of the CCK2 receptor. Gastroenterology, 124(3): 615-25, 2003.



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