T1186 Loss of RKIP Expression is Associated With Metastasis in Esophageal Adenocarcinoma

Abstract

The PTEN phosphatase acts on phosphatidylinositols resulting from phosphatidylinositol 3-kinase (PI3K) activation. Germinal inactive mutations of PTEN have been identified in Cowden syndrome, a disease characterized by the development of hamartomatous polyps in the digestive tract and associated with an increased risk of cancer. However, little is known about the specific cellular role of PTEN in human intestinal epithelial cells. Objective. To investigate the role of PTEN in human colorectal cancer cells. Methods. PTEN expression was analyzed by Western blot in human colorectal tumours, in normal epithelial crypt cells (HIEC) and in many colorectal cancer cell lines: Caco-2/15, DLD-1, HCT116, HT29, LoVo, Colo205 and SW480. Caco-2/15, HCT116 and CT-26 cells were infected with recombinant lentiviruses expressing a shRNA that specifically knocked-down PTEN. The impact of PTEN downregulation was analyzed on cell migration (wound assay), invasion (matrigel-coated transwells) and on tumour and metastasis formation in mice. Results. 1PTEN expression is decreased in approximately 60% of all colon cancer tumours of all grades. 2PTEN is expressed in all cancer cell lines but at a lower level than normal human intestinal epithelial cells. 3The lentiviral infection of PTEN shRNA significantly increases spreading, migration and invasion capacities of Caco-2/15 and HCT116 cells. 4PTEN downregulation in both Caco-2/15 and HCT116 cells increases tumour size following subcutaneous injection of these cells in nude mice. 5Loss of PTEN expression in CT-26 (mouse colorectal cancer cells) leads to an increase in their metastatic potential following tail-vein and intrasplenic injections in BALB/c mice. Conclusions. Altogether, these results indicate that PTEN is involved in the control of migration/invasion capacity and tumorigenic/metastatic potential of human colon cancer cells. Supported by CIHR Team grant.