Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Gastroenterology
Published in: BMC Gastroenterology 1/2008

Open Access 01-12-2008 | Research article

Multilayered epithelium in a rat model and human Barrett's esophagus: Similar expression patterns of transcription factors and differentiation markers

Authors: Xiaoxin Chen, Rong Qin, Ba Liu, Yan Ma, Yinghao Su, Chung S Yang, Jonathan N Glickman, Robert D Odze, Nicholas J Shaheen

Published in: BMC Gastroenterology | Issue 1/2008

Login to get access

Abstract

Background

In rats, esophagogastroduodenal anastomosis (EGDA) without concomitant chemical carcinogen treatment leads to gastroesophageal reflux disease, multilayered epithelium (MLE, a presumed precursor in intestinal metaplasia), columnar-lined esophagus, dysplasia, and esophageal adenocarcinoma. Previously we have shown that columnar-lined esophagus in EGDA rats resembled human Barrett's esophagus (BE) in its morphology, mucin features and expression of differentiation markers (Lab. Invest. 2004;84:753–765). The purpose of this study was to compare the phenotype of rat MLE with human MLE, in order to gain insight into the nature of MLE and its potential role in the development of BE.

Methods

Serial sectioning was performed on tissue samples from 32 EGDA rats and 13 patients with established BE. Tissue sections were immunohistochemically stained for a variety of transcription factors and differentiation markers of esophageal squamous epithelium and intestinal columnar epithelium.

Results

We detected MLE in 56.3% (18/32) of EGDA rats, and in all human samples. As expected, both rat and human squamous epithelium, but not intestinal metaplasia, expressed squamous transcription factors and differentiation markers (p63, Sox2, CK14 and CK4) in all cases. Both rat and human intestinal metaplasia, but not squamous epithelium, expressed intestinal transcription factors and differentiation markers (Cdx2, GATA4, HNF1α, villin and Muc2) in all cases. Rat MLE shared expression patterns of Sox2, CK4, Cdx2, GATA4, villin and Muc2 with human MLE. However, p63 and CK14 were expressed in a higher proportion of rat MLE compared to humans.

Conclusion

These data indicate that rat MLE shares similar properties to human MLE in its expression pattern of these markers, not withstanding small differences, and support the concept that MLE may be a transitional stage in the metaplastic conversion of squamous to columnar epithelium in BE.
Appendix
Available only for authorised users
Literature
1.
Chen X, Yang CS: Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention. Carcinogenesis. 2001, 22 (8): 1119-1129. 10.1093/carcin/22.8.1119.CrossRefPubMed
2.
Guillem PG: How to make a Barrett esophagus: pathophysiology of columnar metaplasia of the esophagus. Dig Dis Sci. 2005, 50 (3): 415-424. 10.1007/s10620-005-2451-x.CrossRefPubMed
3.
Orlando RC: Pathogenesis of reflux esophagitis and Barrett's esophagus. Med Clin North Am. 2005, 89 (2): 219-41, vii. 10.1016/j.mcna.2004.08.006.CrossRefPubMed
4.
Shaheen NJ: Advances in Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology. 2005, 128 (6): 1554-1566. 10.1053/j.gastro.2005.03.032.CrossRefPubMed
5.
Jankowski JA, Harrison RF, Perry I, Balkwill F, Tselepis C: Barrett's metaplasia. Lancet. 2000, 356 (9247): 2079-2085. 10.1016/S0140-6736(00)03411-5.CrossRefPubMed
6.
Fitzgerald RC: Barrett's oesophagus and oesophageal adenocarcinoma: how does acid interfere with cell proliferation and differentiation?. Gut. 2005, 54 Suppl 1: i21-6. 10.1136/gut.2004.041558.CrossRefPubMed
7.
Wong NA, Wilding J, Bartlett S, Liu Y, Warren BF, Piris J, Maynard N, Marshall R, Bodmer WF: CDX1 is an important molecular mediator of Barrett's metaplasia. Proc Natl Acad Sci U S A. 2005, 102 (21): 7565-7570. 10.1073/pnas.0502031102.CrossRefPubMedPubMedCentral
8.
Tselepis C, Perry I, Dawson C, Hardy R, Darnton SJ, McConkey C, Stuart RC, Wright N, Harrison R, Jankowski JA: Tumour necrosis factor-alpha in Barrett's oesophagus: a potential novel mechanism of action. Oncogene. 2002, 21 (39): 6071-6081. 10.1038/sj.onc.1205731.CrossRefPubMed
9.
Kazumori H, Ishihara S, Rumi MA, Kadowaki Y, Kinoshita Y: Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett's epithelium. Gut. 2006, 55 (1): 16-25. 10.1136/gut.2005.066209.CrossRefPubMedPubMedCentral
10.
Marchetti M, Caliot E, Pringault E: Chronic acid exposure leads to activation of the cdx2 intestinal homeobox gene in a long-term culture of mouse esophageal keratinocytes. J Cell Sci. 2003, 116 (Pt 8): 1429-1436. 10.1242/jcs.00338.CrossRefPubMed
11.
Eda A, Osawa H, Satoh K, Yanaka I, Kihira K, Ishino Y, Mutoh H, Sugano K: Aberrant expression of CDX2 in Barrett's epithelium and inflammatory esophageal mucosa. J Gastroenterol. 2003, 38 (1): 14-22. 10.1007/s005350300001.CrossRefPubMed
12.
Boch JA, Shields HM, Antonioli DA, Zwas F, Sawhney RA, Trier JS: Distribution of cytokeratin markers in Barrett's specialized columnar epithelium. Gastroenterology. 1997, 112 (3): 760-765. 10.1053/gast.1997.v112.pm9041237.CrossRefPubMed
13.
Upton MP, Nishioka NS, Ransil BJ, Rosenberg SJ, Puricelli WP, Zwas FR, Shields HM: Multilayered epithelium may be found in patients with Barrett's epithelium and dysplasia or adenocarcinoma. Dig Dis Sci. 2006, 51 (10): 1783-1790. 10.1007/s10620-006-9243-9.CrossRefPubMed
14.
Glickman JN, Chen YY, Wang HH, Antonioli DA, Odze RD: Phenotypic characteristics of a distinctive multilayered epithelium suggests that it is a precursor in the development of Barrett's esophagus. Am J Surg Pathol. 2001, 25 (5): 569-578. 10.1097/00000478-200105000-00002.CrossRefPubMed
15.
Glickman JN, Yang A, Shahsafaei A, McKeon F, Odze RD: Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders. Hum Pathol. 2001, 32 (11): 1157-1165. 10.1053/hupa.2001.28951.CrossRefPubMed
16.
Shields HM, Rosenberg SJ, Zwas FR, Ransil BJ, Lembo AJ, Odze R: Prospective evaluation of multilayered epithelium in Barrett's esophagus. Am J Gastroenterol. 2001, 96 (12): 3268-3273. 10.1111/j.1572-0241.2001.05324.x.CrossRefPubMed
17.
Goldstein SR, Yang GY, Curtis SK, Reuhl KR, Liu BC, Mirvish SS, Newmark HL, Yang CS: Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen. Carcinogenesis. 1997, 18 (11): 2265-2270. 10.1093/carcin/18.11.2265.CrossRefPubMed
18.
Chen X, Yang G, Ding WY, Bondoc F, Curtis SK, Yang CS: An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload. Carcinogenesis. 1999, 20 (9): 1801-1808. 10.1093/carcin/20.9.1801.CrossRefPubMed
19.
Su Y, Chen X, Klein M, Fang M, Wang S, Yang CS, Goyal RK: Phenotype of columnar-lined esophagus in rats with esophagogastroduodenal anastomosis: similarity to human Barrett's esophagus. Lab Invest. 2004, 84 (6): 753-765. 10.1038/labinvest.3700079.CrossRefPubMed
20.
Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR: p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 2004, 18 (2): 126-131. 10.1101/gad.1165104.CrossRefPubMedPubMedCentral
21.
Koster MI, Kim S, Roop DR: P63 deficiency: a failure of lineage commitment or stem cell maintenance?. J Investig Dermatol Symp Proc. 2005, 10 (2): 118-123. 10.1111/j.1087-0024.2005.200416.x.CrossRefPubMed
22.
Carroll DK, Carroll JS, Leong CO, Cheng F, Brown M, Mills AA, Brugge JS, Ellisen LW: p63 regulates an adhesion programme and cell survival in epithelial cells. Nat Cell Biol. 2006, 8 (6): 551-561. 10.1038/ncb1420.CrossRefPubMed
23.
Daniely Y, Liao G, Dixon D, Linnoila RI, Lori A, Randell SH, Oren M, Jetten AM: Critical role of p63 in the development of a normal esophageal and tracheobronchial epithelium. Am J Physiol Cell Physiol. 2004, 287 (1): C171-81. 10.1152/ajpcell.00226.2003.CrossRefPubMed
24.
Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F: p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999, 398 (6729): 714-718. 10.1038/19539.CrossRefPubMed
25.
Geddert H, Kiel S, Heep HJ, Gabbert HE, Sarbia M: The role of p63 and deltaNp63 (p40) protein expression and gene amplification in esophageal carcinogenesis. Hum Pathol. 2003, 34 (9): 850-856. 10.1016/S0046-8177(03)00342-3.CrossRefPubMed
26.
Roman S, Petre A, Thepot A, Hautefeuille A, Scoazec JY, Mion F, Hainaut P: Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. Am J Physiol Gastrointest Liver Physiol. 2007, 293 (1): G45-53. 10.1152/ajpgi.00583.2006.CrossRefPubMed
27.
Ishii Y, Rex M, Scotting PJ, Yasugi S: Region-specific expression of chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial-mesenchymal interactions. Dev Dyn. 1998, 213 (4): 464-475. 10.1002/(SICI)1097-0177(199812)213:4<464::AID-AJA11>3.0.CO;2-Z.CrossRefPubMed
28.
Kamachi Y, Uchikawa M, Kondoh H: Pairing SOX off: with partners in the regulation of embryonic development. Trends Genet. 2000, 16 (4): 182-187. 10.1016/S0168-9525(99)01955-1.CrossRefPubMed
29.
Williamson KA, Hever AM, Rainger J, Rogers RC, Magee A, Fiedler Z, Keng WT, Sharkey FH, McGill N, Hill CJ, Schneider A, Messina M, Turnpenny PD, Fantes JA, van Heyningen V, FitzPatrick DR: Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. Hum Mol Genet. 2006, 15 (9): 1413-1422. 10.1093/hmg/ddl064.CrossRefPubMed
30.
Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, Yamamura Y, Nakamura S, Tatematsu M: Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. J Cancer Res Clin Oncol. 2004, 130 (3): 135-145. 10.1007/s00432-003-0519-6.CrossRefPubMed
31.
Tsukamoto T, Mizoshita T, Mihara M, Tanaka H, Takenaka Y, Yamamura Y, Nakamura S, Ushijima T, Tatematsu M: Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes. Histopathology. 2005, 46 (6): 649-658. 10.1111/j.1365-2559.2005.02170.x.CrossRefPubMed
32.
Que J, Okubo T, Goldenring JR, Nam KT, Kurotani R, Morrisey EE, Taranova O, Pevny LH, Hogan BL: Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development. 2007, 134 (13): 2521-2531. 10.1242/dev.003855.CrossRefPubMedPubMedCentral
33.
Otsubo T, Akiyama Y, Yuasa Y: Sox2 inhibits growth of gastric epithelial cell lines through cell cycle arrest and apoptosis. Proc AACR. 2007, 48: A1239-
34.
Viaene AI, Baert JH: Expression of cytokeratin mRNAs in normal human esophageal epithelium. Anat Rec. 1995, 241 (1): 88-98. 10.1002/ar.1092410112.CrossRefPubMed
35.
Romano RA, Birkaya B, Sinha S: A functional enhancer of keratin14 is a direct transcriptional target of deltaNp63. J Invest Dermatol. 2007, 127 (5): 1175-1186. 10.1038/sj.jid.5700652.CrossRefPubMed
36.
Guo RJ, Suh ER, Lynch JP: The role of cdx proteins in intestinal development and cancer. Cancer Biol Ther. 2004, 3 (7): 593-601.CrossRefPubMed
37.
Silberg DG, Swain GP, Suh ER, Traber PG: Cdx1 and cdx2 expression during intestinal development. Gastroenterology. 2000, 119 (4): 961-971. 10.1053/gast.2000.18142.CrossRefPubMed
38.
Silberg DG, Furth EE, Taylor JK, Schuck T, Chiou T, Traber PG: CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium. Gastroenterology. 1997, 113 (2): 478-486. 10.1053/gast.1997.v113.pm9247467.CrossRefPubMed
39.
Groisman GM, Amar M, Meir A: Expression of the intestinal marker Cdx2 in the columnar-lined esophagus with and without intestinal (Barrett's) metaplasia. Mod Pathol. 2004, 17 (10): 1282-1288. 10.1038/modpathol.3800182.CrossRefPubMed
40.
Boudreau F, Rings EH, van Wering HM, Kim RK, Swain GP, Krasinski SD, Moffett J, Grand RJ, Suh ER, Traber PG: Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription. Implication for the developmental regulation of the sucrase-isomaltase gene. J Biol Chem. 2002, 277 (35): 31909-31917. 10.1074/jbc.M204622200.CrossRefPubMed
41.
Braunstein EM, Qiao XT, Madison B, Pinson K, Dunbar L, Gumucio DL: Villin: A marker for development of the epithelial pyloric border. Dev Dyn. 2002, 224 (1): 90-102. 10.1002/dvdy.10091.CrossRefPubMed
42.
Park J, Schulz S, Waldman SA: Intestine-specific activity of the human guanylyl cyclase C promoter is regulated by Cdx2. Gastroenterology. 2000, 119 (1): 89-96. 10.1053/gast.2000.8520.CrossRefPubMed
43.
Liu T, Zhang X, So CK, Wang S, Wang P, Yan L, Myers R, Chen Z, Patterson AP, Yang CS, Chen X: Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis. 2007, 28 (2): 488-496. 10.1093/carcin/bgl176.CrossRefPubMed
44.
Hinoi T, Loda M, Fearon ER: Silencing of CDX2 expression in colon cancer via a dominant repression pathway. J Biol Chem. 2003, 278 (45): 44608-44616. 10.1074/jbc.M307435200.CrossRefPubMed
45.
Ishikawa A, Sasaki M, Ohira S, Ohta T, Oda K, Nimura Y, Chen MF, Jan YY, Yeh TS, Nakanuma Y: Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasis. Lab Invest. 2004, 84 (5): 629-638. 10.1038/labinvest.3700087.CrossRefPubMed
46.
Satoh K, Mutoh H, Eda A, Yanaka I, Osawa H, Honda S, Kawata H, Kihira K, Sugano K: Aberrant expression of CDX2 in the gastric mucosa with and without intestinal metaplasia: effect of eradication of Helicobacter pylori. Helicobacter. 2002, 7 (3): 192-198. 10.1046/j.1523-5378.2002.00080.x.CrossRefPubMed
47.
Molkentin JD: The zinc finger-containing transcription factors GATA-4, -5, and -6. Ubiquitously expressed regulators of tissue-specific gene expression. J Biol Chem. 2000, 275 (50): 38949-38952. 10.1074/jbc.R000029200.CrossRefPubMed
48.
Jacobsen CM, Narita N, Bielinska M, Syder AJ, Gordon JI, Wilson DB: Genetic mosaic analysis reveals that GATA-4 is required for proper differentiation of mouse gastric epithelium. Dev Biol. 2002, 241 (1): 34-46. 10.1006/dbio.2001.0424.CrossRefPubMed
49.
Sakamoto N, Fukuda K, Watanuki K, Sakai D, Komano T, Scotting PJ, Yasugi S: Role for cGATA-5 in transcriptional regulation of the embryonic chicken pepsinogen gene by epithelial-mesenchymal interactions in the developing chicken stomach. Dev Biol. 2000, 223 (1): 103-113. 10.1006/dbio.2000.9731.CrossRefPubMed
50.
Odom DT, Zizlsperger N, Gordon DB, Bell GW, Rinaldi NJ, Murray HL, Volkert TL, Schreiber J, Rolfe PA, Gifford DK, Fraenkel E, Bell GI, Young RA: Control of pancreas and liver gene expression by HNF transcription factors. Science. 2004, 303 (5662): 1378-1381. 10.1126/science.1089769.CrossRefPubMedPubMedCentral
51.
Gregory PA, Lewinsky RH, Gardner-Stephen DA, Mackenzie PI: Regulation of UDP glucuronosyltransferases in the gastrointestinal tract. Toxicol Appl Pharmacol. 2004, 199 (3): 354-363. 10.1016/j.taap.2004.01.008.CrossRefPubMed
52.
Kumble S, Omary MB, Fajardo LF, Triadafilopoulos G: Multifocal heterogeneity in villin and Ep-CAM expression in Barrett's esophagus. Int J Cancer. 1996, 66 (1): 48-54. 10.1002/(SICI)1097-0215(19960328)66:1<48::AID-IJC9>3.0.CO;2-Z.CrossRefPubMed
53.
MacLennan AJ, Orringer MB, Beer DG: Identification of intestinal-type Barrett's metaplasia by using the intestine-specific protein villin and esophageal brush cytology. Mol Carcinog. 1999, 24 (2): 137-143. 10.1002/(SICI)1098-2744(199902)24:2<137::AID-MC8>3.0.CO;2-A.CrossRefPubMed
54.
Regalado SP, Nambu Y, Iannettoni MD, Orringer MB, Beer DG: Abundant expression of the intestinal protein villin in Barrett's metaplasia and esophageal adenocarcinomas. Mol Carcinog. 1998, 22 (3): 182-189. 10.1002/(SICI)1098-2744(199807)22:3<182::AID-MC6>3.0.CO;2-N.CrossRefPubMed
55.
Gendler SJ, Spicer AP: Epithelial mucin genes. Annu Rev Physiol. 1995, 57: 607-634. 10.1146/annurev.ph.57.030195.003135.CrossRefPubMed
56.
Kumagai H, Mukaisho K, Sugihara H, Bamba M, Miyashita T, Miwa K, Hattori T: Cell kinetic study on histogenesis of Barrett's esophagus using rat reflux model. Scand J Gastroenterol. 2003, 38 (7): 687-692. 10.1080/00365520310003435.CrossRefPubMed
Metadata
Title
Multilayered epithelium in a rat model and human Barrett's esophagus: Similar expression patterns of transcription factors and differentiation markers
Authors
Xiaoxin Chen
Rong Qin
Ba Liu
Yan Ma
Yinghao Su
Chung S Yang
Jonathan N Glickman
Robert D Odze
Nicholas J Shaheen
Publication date
01-12-2008
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2008
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/1471-230X-8-1

Other articles of this Issue 1/2008

BMC Gastroenterology 1/2008 Go to the issue

Research article

Inverse association between gastroesophageal reflux and blood pressure: Results of a large community based study

Research article

Plasma Pentraxin3 is a Novel Marker for Nonalcoholic Steatohepatitis (NASH)

Research article

Combined written and oral information prior to gastrointestinal endoscopy compared with oral information alone: a randomized trial

Research article

Immunohistochemical testing for Helicobacter Pyloriexistence in neoplasms of the colon

Research article

Type and etiology of liver cirrhosis are not related to the presence of hepatic encephalopathy or health-related quality of life: a cross-sectional study

Research article

Bile reflux index after therapeutic biliary procedures
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits