P63 Deficiency and CDX2 Overexpression Lead to Barrett's-Like Metaplasia in Mouse Esophageal Epithelium

Overview

Journal Dig Dis Sci

Specialty Gastroenterology

Date 2021 Jan 20

PMID 33469811

Citations 3

Authors

Yu Fang

Wenbo Li

Xiaoxin Chen

Affiliations

Soon will be listed here.

Abstract

Background: The cellular origin and molecular mechanisms of Barrett's esophagus (BE) are still controversial. Trans-differentiation is a mechanism characterized by activation of the intestinal differentiation program and inactivation of the squamous differentiation program.

Aims: Renal capsule grafting (RCG) was used to elucidate whether CDX2 overexpression on the basis of P63 deficiency in the esophageal epithelium may generate intestinal metaplasia.

Methods: P63;Villin-Cdx2 embryos were generated by crossing P63 mice with Villin-Cdx2 mice. E18.5 esophagus was xenografted in a renal capsule grafting (RCG) model. At 1, 2, or 4 weeks after RCG, the mouse esophagus was immunostained for a proliferation marker (BrdU), squamous transcription factors (SOX2, PAX9), squamous differentiation markers (CK5, CK4, and CK1), intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6), intestinal columnar epithelial cell markers (A33, CK8), goblet cell marker (MUC2, TFF3), Paneth cell markers (LYZ and SOX9), enteroendocrine cell marker (CHA), and Tuft cell marker (DCAMKL1).

Results: The P63;Villin-Cdx2 RCG esophagus was lined with proliferating PAS/AB+ cuboidal cells and formed an intestinal crypt-like structure. The goblet cell markers (TFF3 and MUC2) and intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6) were expressed although no typical morphology of goblet cells was observed. Other intestinal cell markers including enteroendocrine cell marker (CHA), Paneth cell markers (LYZ and Sox9), and intestinal secretory cell marker (UEA/WGA) were also expressed in the P63;Villin-Cdx2 RCG esophagus. Squamous cell markers (PAX9 and SOX2) were also expressed, suggesting a transitional phenotype.

Conclusion: CDX2 overexpression on the basis of P63 deficiency in esophageal epithelial cells induces Barrett's-like metaplasia in vivo. Additional factors may be needed to drive this transitional phenotype into full-blown BE.

Citing Articles

Tuft Cells: Context- and Tissue-Specific Programming for a Conserved Cell Lineage.

Kotas M, OLeary C, Locksley R Annu Rev Pathol. 2022; 18:311-335.

PMID: 36351364 PMC: 10443898. DOI: 10.1146/annurev-pathol-042320-112212.

PAX9 in Cancer Development.

Chen X, Li Y, Paiboonrungruang C, Li Y, Peters H, Kist R Int J Mol Sci. 2022; 23(10).

PMID: 35628401 PMC: 9147292. DOI: 10.3390/ijms23105589.

New insights into tuft cell formation: Implications for structure-function relationships.

OLeary C, Ma Z, Culpepper T, Novak S, DelGiorno K Curr Opin Cell Biol. 2022; 76:102082.

PMID: 35468541 PMC: 9187611. DOI: 10.1016/j.ceb.2022.102082.

References

Fang Y, Chen H, Hu Y, Djukic Z, Tevebaugh W, Shaheen N . Gastroesophageal reflux activates the NF-κB pathway and impairs esophageal barrier function in mice. Am J Physiol Gastrointest Liver Physiol. 2013; 305(1):G58-65. PMC: 3725692. DOI: 10.1152/ajpgi.00438.2012. View

Gregory P, Lewinsky R, Gardner-Stephen D, Mackenzie P . Coordinate regulation of the human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 genes by hepatocyte nuclear factor 1alpha and the caudal-related homeodomain protein 2. Mol Pharmacol. 2004; 65(4):953-63. DOI: 10.1124/mol.65.4.953. View

Boch J, Shields H, Antonioli D, Zwas F, Sawhney R, Trier J . Distribution of cytokeratin markers in Barrett's specialized columnar epithelium. Gastroenterology. 1997; 112(3):760-5. DOI: 10.1053/gast.1997.v112.pm9041237. View

Wani S, Falk G, Hall M, Gaddam S, Wang A, Gupta N . Patients with nondysplastic Barrett's esophagus have low risks for developing dysplasia or esophageal adenocarcinoma. Clin Gastroenterol Hepatol. 2010; 9(3):220-7. DOI: 10.1016/j.cgh.2010.11.008. View

Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson R . p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999; 398(6729):714-8. DOI: 10.1038/19539. View

Bastide P, Darido C, Pannequin J, Kist R, Robine S, Marty-Double C . Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J Cell Biol. 2007; 178(4):635-48. PMC: 2064470. DOI: 10.1083/jcb.200704152. View

Molkentin J . 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):38949-52. DOI: 10.1074/jbc.R000029200. View

Silberg D, Swain G, Suh E, Traber P . Cdx1 and cdx2 expression during intestinal development. Gastroenterology. 2000; 119(4):961-71. DOI: 10.1053/gast.2000.18142. View

Ikeda H, Sasaki M, Ishikawa A, Sato Y, Harada K, Zen Y . Interaction of Toll-like receptors with bacterial components induces expression of CDX2 and MUC2 in rat biliary epithelium in vivo and in culture. Lab Invest. 2007; 87(6):559-71. DOI: 10.1038/labinvest.3700556. View

10.

Qumseya B, Qumsiyeh Y, Ponniah S, Estores D, Yang D, Johnson-Mann C . Barrett's esophagus after sleeve gastrectomy: a systematic review and meta-analysis. Gastrointest Endosc. 2020; 93(2):343-352.e2. DOI: 10.1016/j.gie.2020.08.008. View

11.

Verzi M, Shin H, Ho L, Liu X, Shivdasani R . Essential and redundant functions of caudal family proteins in activating adult intestinal genes. Mol Cell Biol. 2011; 31(10):2026-39. PMC: 3133364. DOI: 10.1128/MCB.01250-10. View

12.

Piessen G, Jonckheere N, Vincent A, Hemon B, Ducourouble M, Copin M . Regulation of the human mucin MUC4 by taurodeoxycholic and taurochenodeoxycholic bile acids in oesophageal cancer cells is mediated by hepatocyte nuclear factor 1alpha. Biochem J. 2006; 402(1):81-91. PMC: 1783985. DOI: 10.1042/BJ20061461. View

13.

Divine J, McCaul S, Simon T . HNF-1alpha and endodermal transcription factors cooperatively activate Fabpl: MODY3 mutations abrogate cooperativity. Am J Physiol Gastrointest Liver Physiol. 2003; 285(1):G62-72. DOI: 10.1152/ajpgi.00074.2003. View

14.

Benoit Y, Pare F, Francoeur C, Jean D, Tremblay E, Boudreau F . Cooperation between HNF-1alpha, Cdx2, and GATA-4 in initiating an enterocytic differentiation program in a normal human intestinal epithelial progenitor cell line. Am J Physiol Gastrointest Liver Physiol. 2010; 298(4):G504-17. PMC: 2907224. DOI: 10.1152/ajpgi.00265.2009. View

15.

Hu B, Chen H, Liu X, Zhang C, Cole G, Lee J . Transgenic overexpression of cdx1b induces metaplastic changes of gene expression in zebrafish esophageal squamous epithelium. Zebrafish. 2013; 10(2):218-27. PMC: 3673616. DOI: 10.1089/zeb.2012.0784. View

16.

Tamai Y, Nakajima R, Ishikawa T, Takaku K, Seldin M, Taketo M . Colonic hamartoma development by anomalous duplication in Cdx2 knockout mice. Cancer Res. 1999; 59(12):2965-70. View

17.

Wong G, Manfra D, Poulet F, Zhang Q, Josien H, Bara T . Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem. 2004; 279(13):12876-82. DOI: 10.1074/jbc.M311652200. View

18.

Chen X, Qin R, Liu B, Ma Y, Su Y, Yang C . 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. PMC: 2267197. DOI: 10.1186/1471-230X-8-1. View

19.

Morrisey E, Tang Z, Sigrist K, Lu M, Jiang F, Ip H . GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 1998; 12(22):3579-90. PMC: 317242. DOI: 10.1101/gad.12.22.3579. View

20.

Wang X, Ouyang H, Yamamoto Y, Kumar P, Wei T, Dagher R . Residual embryonic cells as precursors of a Barrett's-like metaplasia. Cell. 2011; 145(7):1023-35. PMC: 3125107. DOI: 10.1016/j.cell.2011.05.026. View