P-211 Claudin-16, its clinical and prognostic value in colorectal cancer

Abstract

Claudin-16, also known as CLDN-16 or paracellin-1, plays a major role in tight junction-specific occlusion of the intercellular space, through calcium-independent cell-adhesion activity, and Involved in paracellular magnesium reabsorption. The CLDN16 gene is a protein coding gene, mutations of which are associated with diseases such as Hypomagnesemia 3, renal and primary hypomagnesemia. Among its related pathways are cell junction organization and Blood-Brain Barrier and immune cell transmigration. Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. Evidence has now identified tight junction as key barriers to metastatic disease and cancer progression. We have previously shown that CL16 is associated with survival in breast cancer. The present study explored the expression and relevance of Claudin-16 in human colorectal cancer. Claudin-16 expression levels in human colorectal tumour and normal tissues were quantitatively analysed using gene transcript analyses. Expression was determined against the clinical and pathological parameters and clinical outcome of the patients including recurrence, metastatic disease and deaths related to colorectal cancer. The Mann Whitney U statistical test was utilised for comparisons and logistic regression, with Kaplan-Meier used for survival analyses. Expression of Claudin-16 was significantly reduced in tumour specimens in this colorectal cohort (p=0.0016, tumour n=83; normal n=41). Paired tumour/normal tissues also indicated a significantly reduces expression in tumour samples (p= 0.0287). There was a progressive reduction in Claudin-16 expression with increasing TNM status (p < 0.08). Intriguingly, expression of Claudin-16 was significantly lower in tumours originating in right colon and the rectum (p < 0.034) and expression was reduced in tumours that were both invasive/non-invasive (p < 0.026). When evaluating disease outcome, patients that remained alive and well had higher levels of Claudin-16 when compared to those with local recurrence, metastatic disease and had dies from cancer (p < 0.0238). Kaplan-Meier curves indicated that Clausin-16 was associated with recurrence of disease and death from colorectal cancer (p < 0.042). Claudin-16 has a highly differential expression in colorectal cancer and exhibits properties that in future may enable its use as a possible prognostic indicator.