A novel role for the complement regulator CD46 in epithelial tight junction formation/regulation

A novel Role for the complement regulator CD46 in epithelial tight junction formation/regulation

 

Abstract

Background: The complement regulator CD46 has been shown to play a role in epithelial cell polarization and is overexpressed on epithelial tumor cells. It is clear that our understanding of the many functions of the complement system in health is growing but still not complete. It is therefore to be expected that complement will be connected in the future with additional human diseases. This research project focuses on just such a prediction: We have obtained data suggesting a novel role for CD46 in epithelial cell tight junction regulation and growth induction or restriction.  These data suggest that complement may also play a previously unacknowledged role in another important human disease, colon cancer. Colon cancer is the third most common cancer in the UK with a poor prognosis because of a high mortality and recurrence rate, thus, there is a need to develop better treatments. Methods: 1-Culture PTECS or Caco-2 cells for several days on 24 wells-plates to measure E-cadherin expression, CD46 expression, Cell-proliferation assessed and apoptosis induced in cells. 2- Culture the human kidney proximal tubular epithelial cells (PTECS) or the human intestinal cell line (Caco-2) for several days on transwells to measure Transepithelial resistance (TER) and Beads dextran. Results: we found that CD46 interacts with E-cadherin and SPAK, both vital proteins in the maintenance of epithelial cell layer integrity. Mutations in either protein cause colon cancer or IBD, respectively. Further, we observed that CD46 regulates tight junctions and by this transepithelial resistance and paracellular permeability. Based on these data we hypothesize that complement/CD46 communicates with the E-cadherin/catenin network in epithelial cells (via interaction/activation of SPAK) and contributes to normal epithelial cell barrier integrity. Further, defects in CD46-mediated signals leading to disturbance in its crosstalk with the E-cadherin/catenin network may be a factor in malignant transformation. Conclusion: our study was conducted to ascertain the biological properties of CD46 in a cell-cell adhesion network. We believe that this study helped to further solidify this idea and set the ground for more detailed future studies.