8633

UNC5C

UNC5H3;unc-5 homolog C (C. elegans);UNC5C;unc-5 homolog C (C. elegans)

netrin receptor UNC5C|protein unc-5 homolog 3|protein unc-5 homolog C|unc-5 homolog 3|unc5 (C.elegans homolog) c

4q21-q23

protein-coding

The three mammalian receptors UNC5H1, UNC5H2, and UNC5H3 (also named UNC5A, UNC5B, and UNC5C in human) that belong to the family of the netrin-1 receptors, UNC5H, were initially proposed as mediators of the chemorepulsive effect of netrin-1 on specific axons. However, they were also recently shown to act as dependence receptors. Such receptors induce apoptosis when unbound to their ligand. We show here that the expression of the human UNC5A, UNC5B, or UNC5C is down-regulated in multiple cancers including colorectal, breast, ovary, uterus, stomach, lung, or kidney cancers. In colorectal tumors, this down-regulation is associated with loss of heterozygosity occurring within UNC5A, UNC5B, and UNC5C genes but may also be partially related to epigenetic processes because histone deacetylase inhibitor increased UNC5C expression in various cancer cell lines. Moreover, sequencing of UNC5C gene in patients with colorectal tumors revealed the presence of missense mutations. The lossreduction of expression may be a crucial mechanism for tumorigenicity because the expression of UNC5H1, UNC5H2, or UNC5H3 inhibits tumor cell anchorage-independent growth and invasion. Moreover, these hallmarks of malignant transformation can be restored by netrin-1 addition or apoptosis inhibition. Hence, UNC5H1, UNC5H2, and UNC5H3 receptors may represent tumor suppressors that inhibit tumor extension outside the region of netrin-1 availability by inducing apoptosis.

BACKGROUND: UNC5C, one of the Netrin-1 receptors, belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Recently, two reports indicated that UNC5C methylation was closely associated with loss of gene expression in colorectal cancer. MATERIALS AND METHODS: The methylation status of the UNC5C gene was examined in primary carcinomas and the corresponding normal tissues derived from 49 patients with colorectal cancer using quantitative methylation-specific polymerase chain reaction (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Aberrant methylation of the UNC5C gene was detected in 34 out of the 49 (69%) primary colon carcinomas, suggesting that the aberrant methylation of UNC5C was frequent in colorectal cancer. The clinicopathological data were then tested for correlation with this result. A significantly greater proportion of cases with methylated UNC5C was found in Dukes stage C (p = 0.0380) than in earlier stages. CONCLUSION: UNC5C might act as a tumor suppressor and UNC5C methylation might present a malignant potential in colorectal cancer.