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NF-kappaB regulates netrin-1 expression and affects the conditional tumor suppressive activity of the netrin-1 receptors
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BACKGROUND & AIMS:Netrin-1 was recently proposed to play a crucial role during colorectal tumorigenesis by regulating apoptosis. Because netrin-1 receptors belong to the family of dependence receptors, a selective advantage for a tumor is either to lose netrin-1 receptors or to gain autocrine expression of netrin-1. We have investigated whether netrin-1 is up-regulated in colorectal cancer and have searched for a link between NF-kappaB activation and netrin-1 up-regulation.METHODS:The level of netrin-1, netrin-1 receptors, ie, DCC, UNC5H1, UNC5H2, UNC5H3, and the proinflammatory markers cyclooxygenase-2 and inhibitor of nuclear factor-kappaB (IkappaB) alpha were analyzed in a panel of 59 primary sporadic colorectal carcinomas. Netrin-1 expression was investigated in tumor cells and in mouse colonic crypts in response to NF-kappaB activation but also in a mouse model of inflammation-induced colorectal cancer. Binding of NF-kappaB to netrin-1 promoter and effect of NF-kappaB activation to the proapoptotic activity of UNC5H2 were also analyzed.RESULTS:We show that colorectal tumors with a gain of netrin-1 are tumors that display increased activation of the NF-kappaB pathway. Moreover, netrin-1 up-regulation, which is associated with tumor formation in mice, is observed in mouse colonic crypts in response to NF-kappaB activation but also in a mouse model of inflammation-induced colorectal cancer. We demonstrate that the netrin-1 gene is a direct transcriptional target of NF-kappaB. We show that NF-kappaB-induced netrin-1 expression inhibits proapoptotic activity of the netrin-1 receptors.CONCLUSIONS:We propose that NF-kappaB activation that occurs in response to inflammation confers a selective advantage for tumor development through NF-kappaB-mediated netrin-1 up-regulation.
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