Claudin-4 overexpression in epithelial ovarian cancer is associated with hypomethylation and is a potential target for modulation of tight junction barrier function using a C-terminal fragment of Clostridium perfringens enterotoxin

Neoplasia. 2007 Apr;9(4):304-14. doi: 10.1593/neo.07118.


Background: Claudin-4, a tight junction (TJ) protein and receptor for the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), is overexpressed in epithelial ovarian cancer (EOC). Previous research suggests DNA methylation is a mechanism for claudin-4 overexpression in cancer and that C-CPE acts as an absorption-enhancing agent in claudin-4-expressing cells. We sought to correlate claudin-4 overexpression in EOC with clinical outcomes and TJ barrier function, investigate DNA methylation as a mechanism for overexpression, and evaluate the effect of C-CPE on the TJ.

Methods: Claudin-4 expression in EOC was quantified and correlated with clinical outcomes. Claudin-4 methylation status was determined, and claudin-4-negative cell lines were treated with a demethylating agent. Electric cell-substrate impedance sensing was used to calculate junctional (paracellular) resistance (Rb) in EOC cells after claudin-4 silencing and after C-CPE treatment.

Results: Claudin-4 overexpression in EOC does not correlate with survival or other clinical endpoints and is associated with hypomethylation. Claudin-4 overexpression correlates with Rb and C-CPE treatment of EOC cells significantly decreased Rb in a dose- and claudin-4-dependent noncytotoxic manner.

Conclusions: C-CPE treatment of EOC cells leads to altered TJ function. Further research is needed to determine the potential clinical applications of C-CPE in EOC drug delivery strategies.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Claudin-4
  • Clostridium perfringens / physiology*
  • DNA Methylation* / drug effects
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems / methods
  • Enterotoxins / administration & dosage*
  • Enterotoxins / toxicity
  • Female
  • Humans
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics*
  • Neoplasms, Glandular and Epithelial / drug therapy
  • Neoplasms, Glandular and Epithelial / genetics
  • Neoplasms, Glandular and Epithelial / metabolism*
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / toxicity
  • Tight Junctions / drug effects
  • Tight Junctions / enzymology*
  • Tight Junctions / physiology*


  • CLDN4 protein, human
  • Claudin-4
  • Enterotoxins
  • Membrane Proteins
  • Peptide Fragments
  • enterotoxin, Clostridium