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18. Junctional adhesion molecule-A is a new key regulator in colitis associated colon cancer

S. Vetrano1, E. Sala1, C. Correale1, A. Spinelli1, V. Arena2, A. Malesci1, E. Dejana3, S. Danese1

1Istituto Clinico Humanitas, Rozzano, Italy; 2Institute of Pathology, Catholic University of Rome, Rome, Italy; 3Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

Junctional Adhesion Molecule-A (JAM-A) is a tight junction protein expressed by epithelial and endothelial cells. We have shown previously that JAM-A exerts a crucial role in controlling mucosal homeostasis by regulating the integrity and permeability of the intestinal epithelial barrier function. Emerging evidences have indicated an association between increased tight junction permeability of the colon epithelium and tumor development.

The aim of this study was to investigate the involvement of JAM-A in colitis-associated cancer (CAC).

JAM-A expression was analyzed by confocal microscopy in human colon cancer and control tissues and in four human colon cancer cell lines with distinct metastatic potential: CaCo-2, HT29, HCT116 and SW620. JAM-A/ and WT C57BL/6 mice were treated with azoxymethane and three oral cycles of 1.5% dextran sodium sulphate (DSS) each characterized by 7 days DSS exposure followed by 14 days of water. Mice were monitored daily for weight loss, fecal blood and diarrhea and a disease activity index (DAI) was calculated. The damage of murine colonic mucosa was evaluated by endoscopic and histological scores. The grades of histological mucosal lesion were identified as glandular intraepithelial neoplasia (GIN), indicating small clusters of dysplastic colonic crypts on the mucosal surface, low grade (LG) and high grade (HG) adenomas. Colonic murine sections were also stained for Ki67 and β-catenin expression, and apoptosis analysis was performed by TUNEL assay.

JAM-A protein was found to decrease significantly in human colon cancer surrounding cancer lesions, while no differences were observed in corresponding non-neoplastic mucosa compared to normal tissues. Interestingly, JAM-A expression was very low in HCT116, HT29 and SW620 cell lines compared to Caco-2, with lowest expression in the metastatic colon cancer line SW620. JAM-A−/− mice were significantly more susceptible to CAC as assessed by body weight loss (p < 0.001), DAI (p < 0.001), endoscopic and histological inflammation (p < 0.05). Furthermore, JAM-A/ mice showed a higher (p < 0.01) number of tumor incidence in the distal segment of the colon characterized by a high grade (HG) of differentiation in comparison to WT mice. Additionally, JAM-A−/− mice displayed a significantly higher number of Ki-67-positive epithelial cells and TUNEL activity with increased nuclear localization of β-catenin.

These results demonstrate that the low levels of JAM-A correlate with increased incidence of tumor development and tumor aggressiveness. These findings suggest that epithelial JAM-A is a new regulator of colon cancerogenesis.