Inactivation of the UNC5C Netrin-1 Receptor Is Associated With Tumor Progression in Colorectal Malignancies

Abstract

The UNC5H netrin-1 receptors (UNC5H1-3 also called UNC5A-C) belong to the functional dependence receptors family, which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer a tumor-suppressor activity. Indeed, cells harboring these receptors are thought to be dependent on ligand availability for their survival, thereby inhibiting uncontrolled tumor cell proliferation. We investigate here whether UNC5C acts as a tumor suppressor in colorectal malignancies. The level of UNC5C was analyzed in a panel of 86 primary sporadic colorectal carcinomas. Loss of heterozygosity in the UNC5C locus and epigenetic alterations in the UNC5C promoter were also analyzed. Intestinal tumor progression was monitored in mice bearing both UNC5C and APC1638N mutations, and apoptosis was measured in intestinal tumors developed in UNC5C/APC1638N mutant mice. We show here that UNC5C expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, in mice, inactivation of UNC5C is associated with increased intestinal tumor progression and a decrease in tumor cell apoptosis. The loss of UNC5C expression observed in human colorectal cancer is a selective advantage for tumor progression, in agreement with the dependence receptor hypothesis. Thus, the UNC5C dependence receptor is a tumor suppressor that regulates sporadic colorectal cancer.