Altogether these results suggest that miR-17-3p functions as a tumor suppressor, representing a novel,
new target to block prostate tumor progression. O32 Regulation of Colon Cancer Metastasis by Death Receptor-3 and CDK and cancer E-selectin Nicolas Porquet1, Stéphanie Gout1, Pierre-Luc Tremblay1,2, Andrée Poirier1, François Houle1, François A. Auger2, Jacques Huot 1 1 Le Centre de Entospletinib in vivo Recherche en Cancérologie, Université Laval et CRCHUQ, Québec, QC, Canada, 2 Laboratoire d’Organogenèse Expérimentale, CHA de l’Université Laval, Québec, QC, Canada The adhesion of circulating cancer cells to endothelial cells (EC) is a prerequisite for their extravasation and metastatic dissemination. We have shown that E-selectin, a major endothelial adhesion receptor, interacts with Death Receptor-3 (DR3), present on colon carcinoma cells, to promote their adhesion to EC and to increase their
motile and survival potentials (Gout et al. Cancer Res. 2006 and CEM, 2008). We also found that E-selectin and TL1A, the cognate ligand of DR3, trigger the tyrosine phosphorylation of DR3 in a Src family kinase (SFK)-dependent manner. Moreover, we obtained evidence indicating that interaction between R406 supplier DR3 and E-selectin or TL1A induces the activation of the PI3K/Akt pathway in HT-29 colon carcinoma cells. We further discovered that p65/RelA, the anti-apoptotic subunit of NFkB, is rapidly phosphorylated at Ser 536 in response to E-selectin or TL1A and found that the phosphorylation occurs downstream of PI3K/Akt. Cyclooxygenase (COX) These findings suggest that E-selectin and TL1A induced-activation of DR3 confers a
metastatic advantage to colon cancer cells by inducing SFK-dependent tyrosine phosphorylation of DR3 and by activating the pro-survival PI3K/Akt/NFkBp65 axis. Interestingly, the activation of E-selectin induces a remodeling of EC that is associated with disruption of the adherens junctions. This leads to increased interendothelial spaces enabling transendothelial migration (Tremblay et al Oncogene 2006). Using a laminar flow chamber, we identified three distinct mechanisms by which cancer cells interact with E-selectin to initiate their diapedesis: formation of a mosaic between cancer cells and EC, paracellular diapedesis at the junction of three EC, and transcellular diapedesis (Tremblay et al. Cancer Res. 2008). We conclude that E-selectin-mediated adhesion of colon cancer cells regulates metastasis by conferring inherent invasive potential to cancer cells following binding to DR3 and by remodeling the endothelium in a way that facilitates diapedesis. Supported by the Canadian Cancer Society and the Canadian Institutes for Health Research. NP, SG and PLT have equally contributed to this study.