Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis

Jillian L. Pope, Rizwan Ahmad, Ajaz Ahmad Bhat, Mary K. Washington, Amar B. Singh, Punita Dhawan

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Background: The tight junction protein Claudin-1, a claudin family member, has been implicated in several gastro-intestinal pathologies including inflammatory bowel disease (IBD) and colorectal cancer (CRC). In this regard, we have demonstrated that claudin-1 expression in colon cancer cells potentiates their tumorigenic ability while in vivo expression of claudin-1 in the intestinal epithelial cells (IECs) promotes Notch-activation, inhibits goblet cell differentiation and renders susceptibility to mucosal inflammation. Notably, a key role of inflammation in colon cancer progression is being appreciated. Therefore, we examined whether inflammation plays an important role in claudin-1-dependent upregulation of colon carcinogenesis.Methods: APCmin mice were crossed with Villin-claudin-1 transgenic mice to generate APC-Cldn1 mice. H&E stained colon tissues were assessed for tumor number, size and histological grade. Additionally, microarray and qPCR analyses of colonic tumors were performed to assess molecular changes due to claudin-1 expression. APC-Cldn1 and APCmin controls were assessed for colonic permeability via rectal administration of FITC-dextran, and bacterial translocation via qPCR analysis of 16S rDNA.Results: Claudin-1 overexpression in APCmin mice significantly increased (~4-fold) colonic tumor growth and size, and decreased survival. Furthermore, transcriptome analysis supported upregulated proliferation, and increased Wnt and Notch-signaling in APC-Cldn1 mice. APC-Cldn1 mice also demonstrated inhibition of mucosal defense genes while expression of pro-inflammatory genes was sharply upregulated, especially the IL-23/IL-17 signaling. We predict that increased Notch/Wnt-signaling underlie the early onset of adenoma formation in APC-Cldn1 mice. An increase in mucosal permeability due to the adenomas and the inherent barrier defect in these mice further facilitate bacterial translocation into the mucosa to induce inflammation, which in turn promote the tumorigenesis.Conclusion: Taken together, these results confirm the role of claudin-1 as a promoter of colon tumorigenesis and further identify the role of the dysregulated antigen-tumor interaction and inflammation in claudin-1-dependent upregulation of colon tumorigenesis.

Original languageEnglish
Article number167
JournalMolecular Cancer
Volume13
Issue number1
DOIs
Publication statusPublished - 6 Jul 2014
Externally publishedYes

Fingerprint

Claudin-1
Adenomatous Polyposis Coli
Colon
Carcinogenesis
Epithelial Cells
Inflammation
Bacterial Translocation
Adenoma
Colonic Neoplasms
Permeability
Up-Regulation
Zonula Occludens-1 Protein
Rectal Administration
Interleukin-23
Neoplasms
Aptitude
Goblet Cells
Interleukin-17
Gene Expression Profiling
Neoplasm Antigens

Keywords

  • Bacteria
  • Claudin-1
  • Colorectal cancer
  • IL23
  • Muc2

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis. / Pope, Jillian L.; Ahmad, Rizwan; Bhat, Ajaz Ahmad; Washington, Mary K.; Singh, Amar B.; Dhawan, Punita.

In: Molecular Cancer, Vol. 13, No. 1, 167, 06.07.2014.

Research output: Contribution to journalArticle

Pope, Jillian L. ; Ahmad, Rizwan ; Bhat, Ajaz Ahmad ; Washington, Mary K. ; Singh, Amar B. ; Dhawan, Punita. / Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis. In: Molecular Cancer. 2014 ; Vol. 13, No. 1.
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AU - Singh, Amar B.

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