Claudin-1 Up-Regulates the Repressor ZEB-1 to Inhibit E-cadherin Expression in Colon Cancer Cells

Gastroenterology. 2011 Dec;141(6):2140-53. doi: 10.1053/j.gastro.2011.08.038. Epub 2011 Aug 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anoikis
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Claudin-1
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Immunoblotting
  • Membrane Proteins / physiology*
  • Microarray Analysis
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • CLDN1 protein, human
  • Cadherins
  • Claudin-1
  • Homeodomain Proteins
  • Membrane Proteins
  • RNA, Messenger
  • Transcription Factors
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1