Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells

Amar B. Singh, Ashok Sharma, J. Joshua Smith, Moorthy Krishnan, Xi Chen, Steven Eschrich, Mary K. Washington, Timothy J. Yeatman, R. Daniel Beauchamp, Punita Dhawan

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

Background & Aims: Expression of the tight junction protein claudin-1 is dysregulated in colon tumors and associates with their progression. Up-regulation of claudin-1 reduces expression of E-cadherin. We investigated the mechanisms by which claudin-1 regulates E-cadherin expression and its effects in colon cancer cells. Materials and Methods: We used gene expression analysis, immunoblotting, and reverse transcription polymerase chain reaction to associate expression of the repressor of transcription Zinc Finger E-box binding homeobox-box1 (ZEB-1) with claudin-1. We analyzed SW480 colon cancer cells that overexpressed claudin-1, or SW620 cells in which claudin-1 expression was repressed, to determine the effects on ZEB-1 and E-cadherin expression, invasive activity, and resistance to anoikis. We studied cells that expressed constitutively active or dominant negative forms of factors in the Wnt or phosphotidylinositol-3-kinase signaling pathways and used pharmacologic inhibitors of these pathways to study their role in claudin-1-dependent regulation of ZEB-1. We used microarray analysis to examine gene expression patterns in 260 colorectal tumor and normal colon samples. Results: Claudin-1 down-regulates E-cadherin expression by up-regulating expression of ZEB-1. Claudin-1 activates Wnt and phosphotidylinositol-3-kinase/Akt signaling. ZEB-1 mediates claudin-1-regulated changes in cell invasion and anoikis. Expression of claudin-1 correlated with that of ZEB-1 in human colon tumor samples. In the progression from normal colonic epithelium to colon adenocarcinoma, levels of E-cadherin decreased, whereas levels of claudin-1 and ZEB-1 increased. Down-regulation of E-cadherin and up-regulation of ZEB-1 in colon tumors were associated with shorter survival times. Conclusions: Claudin-1 up-regulates the repressor ZEB-1 to reduce expression of E-cadherin in colon cancer cells, increasing their invasive activity and reducing anoikis. This pathway is associated with colorectal cancer progression and patient survival.

Original languageEnglish (US)
Pages (from-to)2140-2153
Number of pages14
JournalGastroenterology
Volume141
Issue number6
DOIs
StatePublished - Dec 2011

Keywords

  • Colorectal Cancer
  • Gene Regulation
  • Prognostic Factor
  • Signal Transduction
  • Transcription Factor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Singh, A. B., Sharma, A., Smith, J. J., Krishnan, M., Chen, X., Eschrich, S., Washington, M. K., Yeatman, T. J., Beauchamp, R. D., & Dhawan, P. (2011). Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells. Gastroenterology, 141(6), 2140-2153. https://doi.org/10.1053/j.gastro.2011.08.038