Background & Aims: DCC and UNC5C, Netrin-1 dependence receptors, perform an important role in intestinal epithelial biology. Both receptors frequently are down-regulated in colorectal cancer (CRC). Although CRCs frequently lose DCC owing to deletions at 18q, the mechanism for the UNC5C loss is poorly understood. We hypothesized that UNC5C is silenced epigenetically in CRC, and that there are interactions between losses of UNC5C and DCC in colorectal tumorigenesis. Methods: Gene expression and epigenetic analysis of UNC5C was examined in 8 CRC cell lines, 147 sporadic CRCs with corresponding normal mucosa, and 52 adenomatous polyps (APs). Allelic imbalances at DCC were determined in CRCs. The molecular analyses were compared with genetic and clinicopathologic features. Results: All CRC cell lines showed UNC5C methylation and an associated loss of gene expression. Treatment with 5-Aza-2'-deoxycytidine resulted in restoration of gene transcription. UNC5C methylation was significantly higher in CRCs (76.2%) and APs (63.5%) than in corresponding normal mucosa (6%; P < .0001). Allelic imbalance at DCC was observed in 61% of CRCs. Overall, 89.3% of CRCs had alterations of one of the dependence receptors. UNC5C methylation occurred predominantly in the earlier lesions (APs and early CRCs), whereas DCC losses were more often in advanced CRCs. Conclusions: The majority of CRCs harbor defects in Netrin-1 receptors, emphasizing the importance of this growth regulatory pathway in cancer. Furthermore, the timing of the molecular alterations in the Netrin-1 receptors is not random because UNC5C inactivation occurs early, whereas DCC losses occurs in later stages of multistep colorectal carcinogenesis.
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