nach oben

Journal of Gastroenterology

Erschienen in:

01.09.2009 | Original Article—Alimentary Tract

Differential gene expression in normal esophagus and Barrett’s esophagus

verfasst von: Jacob Wang, Rong Qin, Yan Ma, Huiyun Wu, Heiko Peters, Matthew Tyska, Nicholas J. Shaheen, Xiaoxin Chen

Erschienen in: Journal of Gastroenterology | Ausgabe 9/2009

Einloggen, um Zugang zu erhalten

Abstract

Purpose

As the premalignant lesion of human esophageal adenocarcinoma (EAC), Barrett’s esophagus (BE) is characterized by intestinal metaplasia in the normal esophagus (NE). Gene expression profiling with microarray and serial analysis of gene expression (SAGE) may help us understand the potential molecular mechanism of human BE.

Methods

We analyzed three microarray datasets (two cDNA arrays and one oligonucleotide array) and one SAGE dataset with statistical tools, significance analysis of microarrays (SAM) and SAGE(Poisson), to identify individual genes differentially expressed in BE. Gene set enrichment analysis (GSEA) was used to identify a priori defined sets of genes that were differentially expressed. These gene sets were grouped according to either certain signaling pathways (GSEA curated), or the presence of consensus binding sequences of known transcription factors (GSEA motif). Immunohistochemical staining (IHC) was used to validate differential gene expression.

Results

Both SAM and SAGE(Poisson) identified 68 differentially expressed genes (55 BE genes and 13 NE genes) with an arbitrary cutoff ratio (≥4-fold). With IHC on matched pairs of NE and BE tissues from 6 patients, these genes were grouped into 6 categories: category I (25 genes only expressed in BE), category II (5 genes only expressed in NE), category III (8 genes expressed more in BE than in NE), and category IV (2 genes expressed more in NE than in BE). Differential expression of the remaining genes was not confirmed by IHC either due to false discovery (category V), or lack of proper antibodies (category VI). Besides individual genes, the TGFβ pathway and several transcription factors (CDX2, HNF1, and HNF4) were identified by GSEA as enriched pathways and motifs in BE. Apart from 9 target genes known to be up-regulated in BE, IHC staining confirmed up-regulation of 19 additional CDX1 and CDX2 target genes in BE.

Conclusion

Our data suggested an important role of CDX1 and CDX2 in the development of BE. The IHC-confirmed gene list will lead to future studies on the molecular mechanism of BE.

Nur mit Berechtigung zugänglich

Chen X, Yang CS. Esophageal adenocarcinoma: a review and perspectives on the mechanism of carcinogenesis and chemoprevention. Carcinogenesis. 2001;22:1119–29.PubMedCrossRef

Jankowski JA, Harrison RF, Perry I, Balkwill F, Tselepis C. Barrett’s metaplasia. Lancet. 2000;356:2079–85.PubMedCrossRef

Fitzgerald RC. Barrett’s oesophagus and oesophageal adenocarcinoma: how does acid interfere with cell proliferation and differentiation? Gut. 2005;54(Suppl 1):i21–6.PubMedCrossRef

Krishnadath KK. Novel findings in the pathogenesis of esophageal columnar metaplasia or Barrett’s esophagus. Curr Opin Gastroenterol. 2007;23:440–5.PubMedCrossRef

van Baal JW, Krishnadath KK. High throughput techniques for characterizing the expression profile of Barrett’s esophagus. Dis Esophagus. 2008;21:634–40.PubMedCrossRef

Barrett MT, Yeung KY, Ruzzo WL, Hsu L, Blount PL, Sullivan R, et al. Transcriptional analyses of Barrett’s metaplasia and normal upper GI mucosae. Neoplasia. 2002;4:121–8.PubMedCrossRef

Fox CA, Sapinoso LM, Zhang H, Zhang W, McLeod HL, Petroni GR, et al. Altered expression of TFF-1 and CES-2 in Barrett’s esophagus and associated adenocarcinomas. Neoplasia. 2005;7:407–16.PubMedCrossRef

Gomes LI, Esteves GH, Carvalho AF, Cristo EB, Hirata R Jr, Martins WK, et al. Expression profile of malignant and nonmalignant lesions of esophagus and stomach: differential activity of functional modules related to inflammation and lipid metabolism. Cancer Res. 2005;65:7127–36.PubMedCrossRef

Greenawalt DM, Duong C, Smyth GK, Ciavarella ML, Thompson NJ, Tiang T, et al. Gene expression profiling of esophageal cancer: comparative analysis of Barrett’s esophagus, adenocarcinoma, and squamous cell carcinoma. Int J Cancer. 2007;120:1914–21.PubMedCrossRef

10.

Hao Y, Triadafilopoulos G, Sahbaie P, Young HS, Omary MB, Lowe AW. Gene expression profiling reveals stromal genes expressed in common between Barrett’s esophagus and adenocarcinoma. Gastroenterology. 2006;131:925–33.PubMedCrossRef

11.

Helm J, Enkemann SA, Coppola D, Barthel JS, Kelley ST, Yeatman TJ. Dedifferentiation precedes invasion in the progression from Barrett’s metaplasia to esophageal adenocarcinoma. Clin Cancer Res. 2005;11:2478–85.PubMedCrossRef

12.

Kimchi ET, Posner MC, Park JO, Darga TE, Kocherginsky M, Karrison T, et al. Progression of Barrett’s metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation. Cancer Res. 2005;65:3146–54.PubMed

13.

Ostrowski J, Mikula M, Karczmarski J, Rubel T, Wyrwicz LS, Bragoszewski P, et al. Molecular defense mechanisms of Barrett’s metaplasia estimated by an integrative genomics. J Mol Med. 2007;85:733–43.PubMedCrossRef

14.

Ostrowski J, Rubel T, Wyrwicz LS, Mikula M, Bielasik A, Butruk E, et al. Three clinical variants of gastroesophageal reflux disease form two distinct gene expression signatures. J Mol Med. 2006;84:872–82.PubMedCrossRef

15.

Pohler E, Craig AL, Cotton J, Lawrie L, Dillon JF, Ross P, et al. The Barrett’s antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage. Mol Cell Proteomics. 2004;3:534–47.PubMedCrossRef

16.

Selaru FM, Zou T, Xu Y, Shustova V, Yin J, Mori Y, et al. Global gene expression profiling in Barrett’s esophagus and esophageal cancer: a comparative analysis using cDNA microarrays. Oncogene. 2002;21:475–8.PubMedCrossRef

17.

van Baal JW, Milano F, Rygiel AM, Bergman JJ, Rosmolen WD, van Deventer SJ, et al. A comparative analysis by SAGE of gene expression profiles of Barrett’s esophagus, normal squamous esophagus, and gastric cardia. Gastroenterology. 2005;129:1274–81.PubMedCrossRef

18.

Wang S, Zhan M, Yin J, Abraham JM, Mori Y, Sato F, et al. Transcriptional profiling suggests that Barrett’s metaplasia is an early intermediate stage in esophageal adenocarcinogenesis. Oncogene. 2006;25:3346–56.PubMedCrossRef

19.

Xu Y, Selaru FM, Yin J, Zou TT, Shustova V, Mori Y, et al. Artificial neural networks and gene filtering distinguish between global gene expression profiles of Barrett’s esophagus and esophageal cancer. Cancer Res. 2002;62:3493–7.PubMed

20.

van Baal JW, Diks SH, Wanders RJ, Rygiel AM, Milano F, Joore J, et al. Comparison of kinome profiles of Barrett’s esophagus with normal squamous esophagus and normal gastric cardia. Cancer Res. 2006;66:11605–12.PubMedCrossRef

21.

Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA. 2001;98:5116–21.PubMedCrossRef

22.

Cai L, Huang H, Blackshaw S, Liu JS, Cepko C, Wong WH. Clustering analysis of SAGE data using a Poisson approach. Genome Biol. 2004;5:R51.PubMedCrossRef

23.

Lewin K, Appelman H. Barrett’s esophagus, columnar dysplasia, and adenocarcinoma of the esophagus. In: Appelman KLaH, editor. Tumors of the Esophagus and Stomach. Washington: AFIP; 1995. p. 99–144.

24.

Liu T, Zhang X, So CK, Wang S, Wang P, Yan L, et al. Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells. Carcinogenesis. 2007;28:488–96.PubMedCrossRef

25.

Wong NA, Wilding J, Bartlett S, Liu Y, Warren BF, Piris J, et al. CDX1 is an important molecular mediator of Barrett’s metaplasia. Proc Natl Acad Sci USA. 2005;102:7565–70.PubMedCrossRef

26.

Yang Q, Bermingham NA, Finegold MJ, Zoghbi HY. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science. 2001;294:2155–8.PubMedCrossRef

27.

Eda A, Osawa H, Satoh K, Yanaka I, Kihira K, Ishino Y, et al. Aberrant expression of CDX2 in Barrett’s epithelium and inflammatory esophageal mucosa. J Gastroenterol. 2003;38:14–22.PubMedCrossRef

28.

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;113:478–86.PubMedCrossRef

29.

Chen X, Qin R, Liu B, Ma Y, Su Y, Yang CS, et al. Multilayered epithelium in a rat model and human Barrett’s esophagus: similar expression patterns of transcription factors and differentiation markers. BMC Gastroenterol. 2008;8:1.PubMedCrossRef

30.

Milano F, van Baal JW, Buttar NS, Rygiel AM, de Kort F, DeMars CJ, et al. Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells. Gastroenterology. 2007;132:2412–21.PubMedCrossRef

31.

Slack JM, Tosh D. Transdifferentiation and metaplasia—switching cell types. Curr Opin Genet Dev. 2001;11:581–6.PubMedCrossRef

32.

Brabender J, Marjoram P, Salonga D, Metzger R, Schneider PM, Park JM, et al. A multigene expression panel for the molecular diagnosis of Barrett’s esophagus and Barrett’s adenocarcinoma of the esophagus. Oncogene. 2004;23:4780–8.PubMedCrossRef

33.

Glickman JN, Blount PL, Sanchez CA, Cowan DS, Wongsurawat VJ, Reid BJ, et al. Mucin core polypeptide expression in the progression of neoplasia in Barrett’s esophagus. Hum Pathol. 2006;37:1304–15.PubMedCrossRef

34.

Jovov B, Van Itallie CM, Shaheen NJ, Carson JL, Gambling TM, Anderson JM, et al. Claudin-18: a dominant tight junction protein in Barrett’s esophagus and likely contributor to its acid resistance. Am J Physiol Gastrointest Liver Physiol. 2007;293:G1106–13.PubMedCrossRef

35.

Kumble S, Omary MB, Fajardo LF, Triadafilopoulos G. Multifocal heterogeneity in villin and Ep-CAM expression in Barrett’s esophagus. Int J Cancer. 1996;66:48–54.PubMedCrossRef

36.

Madsen J, Nielsen O, Tornoe I, Thim L, Holmskov U. Tissue localization of human trefoil factors 1, 2, and 3. J Histochem Cytochem. 2007;55:505–13.PubMedCrossRef

37.

Mitas M, Almeida JS, Mikhitarian K, Gillanders WE, Lewin DN, Spyropoulos DD, et al. Accurate discrimination of Barrett’s esophagus and esophageal adenocarcinoma using a quantitative three-tiered algorithm and multimarker real-time reverse transcription-PCR. Clin Cancer Res. 2005;11:2205–14.PubMedCrossRef

38.

van Baal JW, Bozikas A, Pronk R, Ten Kate FJ, Milano F, Rygiel AM, et al. Cytokeratin and CDX-2 expression in Barrett’s esophagus. Scand J Gastroenterol. 2008;43:132–40.PubMedCrossRef

39.

Wong NA, Warren BF, Piris J, Maynard N, Marshall R, Bodmer WF. EpCAM and gpA33 are markers of Barrett’s metaplasia. J Clin Pathol. 2006;59:260–3.PubMedCrossRef

40.

Christie KN, Thomson C. The distribution of carbonic anhydrase II in human, pig and rat oesophageal epithelium. Histochem J. 2000;32:753–7.PubMedCrossRef

41.

Xia SH, Hu LP, Hu H, Ying WT, Xu X, Cai Y, et al. Three isoforms of annexin I are preferentially expressed in normal esophageal epithelia but down-regulated in esophageal squamous cell carcinomas. Oncogene. 2002;21:6641–8.PubMedCrossRef

42.

Mobasheri A, Wray S, Marples D. Distribution of AQP2 and AQP3 water channels in human tissue microarrays. J Mol Histol. 2005;36:1–14.PubMedCrossRef

43.

Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology. 2002;40:403–39.PubMedCrossRef

44.

Gerber JK, Richter T, Kremmer E, Adamski J, Hofler H, Balling R, et al. Progressive loss of PAX9 expression correlates with increasing malignancy of dysplastic and cancerous epithelium of the human oesophagus. J Pathol. 2002;197:293–7.PubMedCrossRef

45.

Ihrie RA, Marques MR, Nguyen BT, Horner JS, Papazoglu C, Bronson RT, et al. Perp is a p63-regulated gene essential for epithelial integrity. Cell. 2005;120:843–56.PubMedCrossRef

46.

South AP. Plakophilin 1: an important stabilizer of desmosomes. Clin Exp Dermatol. 2004;29:161–7.PubMedCrossRef

47.

Nishimori T, Tomonaga T, Matsushita K, Oh-Ishi M, Kodera Y, Maeda T, et al. Proteomic analysis of primary esophageal squamous cell carcinoma reveals downregulation of a cell adhesion protein, periplakin. Proteomics. 2006;6:1011–8.PubMedCrossRef

48.

Mori-Akiyama Y, van den Born M, van Es JH, Hamilton SR, Adams HP, Zhang J, et al. SOX9 is required for the differentiation of paneth cells in the intestinal epithelium. Gastroenterology. 2007;133:539–46.PubMedCrossRef

49.

Niimi T, Nagashima K, Ward JM, Minoo P, Zimonjic DB, Popescu NC. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. 2001;21:7380–90.PubMedCrossRef

50.

Haveri H, Westerholm-Ormio M, Lindfors K, Maki M, Savilahti E, Andersson LC, et al. Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa. BMC Gastroenterol. 2008;8:9.PubMedCrossRef

51.

Calon A, Gross I, Lhermitte B, Martin E, Beck F, Duclos B, et al. Different effects of the Cdx1 and Cdx2 homeobox genes in a murine model of intestinal inflammation. Gut. 2007;56:1688–95.PubMedCrossRef

52.

Barros R, Pereira B, Duluc I, Azevedo M, Mendes N, Camilo V, et al. Key elements of the BMP/SMAD pathway co-localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines. J Pathol. 2008.

Titel: Differential gene expression in normal esophagus and Barrett’s esophagus
verfasst von: Jacob Wang
Rong Qin
Yan Ma
Huiyun Wu
Heiko Peters
Matthew Tyska
Nicholas J. Shaheen
Xiaoxin Chen
Publikationsdatum: 01.09.2009
Verlag: Springer Japan
Erschienen in: Journal of Gastroenterology / Ausgabe 9/2009
Print ISSN: 0944-1174
Elektronische ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-009-0082-2

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Differential gene expression in normal esophagus and Barrett’s esophagus

Abstract

Purpose

Methods

Results

Conclusion

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 9/2009

Dietary olive oil prevents carbon tetrachloride-induced hepatic fibrosis in mice

The influence of hepatitis B DNA level and antiviral therapy on recurrence after initial curative treatment in patients with hepatocellular carcinoma

Influence of adiponectin gene polymorphisms in Japanese patients with non-alcoholic fatty liver disease

Predictive values of amino acid sequences of the core and NS5A regions in antiviral therapy for hepatitis C: a Japanese multi-center study

Low-dose aspirin is a prominent cause of bleeding ulcers in patients who underwent emergency endoscopy

Present status and strategy of NSAIDs-induced small bowel injury

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin