Role of E-Cadherin and Beta-Catenin in Colorectal Cancer Progression
DT Leahy, M Milewski, E Fox, R Geraghty, H Mulcahy, J Hyland, D O'Donoghue, K Sheahan. University College Dublin, Dublin, Ireland; Centre for Colorectal Disease, St. Vincent's University Hospital, Dublin, Ireland
Background: The adherens junction is the region of the cell membrane which is vital in the maintenance of normal cellular morphology. Reduced cellular adhesiveness facilitates cancer invasion and metastasis. E-cadherin forms an adherens complex in the cell membrane with beta-catenin and alpha-catenin. Beta-catenin may also translocate from the cell membrane to the nucleus where it acts in the dysregulation of the Wnt signalling pathway which plays an important role in colorectal cancer.
Design: The study cohort consisted of 109 sporadic colorectal cancers with full clinicopathological data. Microsatellite instability testing was performed using the National Cancer Institute consensus panel of five microsatellite markers. Tumors displaying instability in at least 2 of 5 markers were regarded as having high-level microsatellite instability (MSI-H). Expression of E-cadherin and beta-catenin was assessed by immunohistochemistry. E-cadherin was scored for membrane staining. Beta-catenin was scored for membrane, cytoplasmic and nuclear staining. E-cadherin gene promoter hypermethylation was investigated using methylation specific PCR. All results were correlated with patients' clinicopathological features.
Results: There was a strong positive association between E-cadherin gene promoter hypermethylation and decreased E-cadherin expression in the cell membrane (p<0.001). E-cadherin methylation also correlated with the presence of distant metastasis (p<0.001). Reduced expression of E-cadherin in the tumor cell membrane was associated with increased nuclear beta-catenin expression (p=0.047). Beta-catenin nuclear accumulation was indicative of distant metastasis (p=0.046). Membranous beta-catenin staining correlated with microsatellite unstable (MSI-H) tumors (p=0.02) and with right-sided location of tumors (p=0.005).
Conclusions: Loss of membranous E-cadherin and increased nuclear beta-catenin localization are associated with advanced colorectal cancer. The mechanism of loss of E-cadherin expresssion in advanced colorectal cancer appears to be silencing of the E-cadherin gene due to hypermethylation of its promoter.
Monday, March 9, 2009 1:00 PM
Poster Session II # 72, Monday Afternoon