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

Abstract

Background & Aims-The UNC5H netrin-1 receptors (UNC5H1-3, or UNC5A-C) belong to the functional dependence receptors family that 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.

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…UNC5C is indeed the most downregulated member of the UNC5H family (74-77% of cases, A new paradigm in cell signaling and cancer therapy D Goldschneider and P Mehlen whereas UNC5H1/UNC5A and H2/B show a reduced expression in 48 and 27% of the cases, respectively). This loss of expression observed in human primary tumors, as well as in cell lines, is essentially due to promoter methylation (Bernet et al, 2007;Shin et al, 2007). Furthermore, Bernet and colleagues took advantage of a natural UNC5H3 loss-of-function occurring in mice (rcm, rostral cerebellar malformation) to demonstrate that UNC5H3 loss of function is associated with tumor progression: mice that carry the APC 1638N germline mutation, known to predispose mice to the development of low-grade adenoma (Sieber et al, 2000), and are heterozygous or homozygous for mutant UNC5H3, develop adenomas that progress to adenocarcinoma at a higher frequency than what is seen in APC 1638N mice.…”

Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression

“…Expression of Netrin-1, -3, and -4 genes in human tumoral cell lines was normalized to hypoxanthineguanine phosphoribosyltransferase (HPRT) gene. Netrin-1 expression in human IBD patients was normalized to the ubiquitously expressed retinoid X receptor alfa (RXR␣) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) genes, that showed less variability in expression between normal and colorectal tumoral tissues (9). The amount of target transcripts, normalized to the housekeeping gene, was calculated using the comparative C T method.…”

“…Along this line, both overexpression of netrin-1 or inactivation of UNC5H3 in mice in the gastro-intestinal tract are associated with intestinal tumor progression (3,9). Even though according to the dependence receptor hypothesis, a loss of netrin-1 receptors should represent a similar selective advantage for tumor growth than gaining autocrine expression of netrin-1, in sporadic colorectal cancer the vast majority of tumors display a loss of DCC or/and UNC5H (9)(10)(11)(12).…”

“…Even though according to the dependence receptor hypothesis, a loss of netrin-1 receptors should represent a similar selective advantage for tumor growth than gaining autocrine expression of netrin-1, in sporadic colorectal cancer the vast majority of tumors display a loss of DCC or/and UNC5H (9)(10)(11)(12). In these tumors with decreased receptors expression, netrin-1 is not up-regulated and is barely detectable within the tumors [ (Fig.…”

Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability

“…This loss of apoptosis as a selective advantage for tumor development could, in the context of dependence receptors, be conferred by at least two events: either by losing receptor expression or by gaining netrin-1 expression. As a matter of fact, DCC and UNC5 receptors are down-regulated in numerous human cancers (9). On the other hand, netrin-1 functions as an oncogene and is up-regulated in various kinds of cancers (10).…”