Abstract
BackgroundDeregulated methylation of tumor suppressor genes is a hallmark event in colorectal cancer (CRC) carcinogenesis. UNC5 receptors, down-regulated in various human malignancies due to epigenetic alterations, have been proposed as putative tumor suppressor genes. In this study, we focused on the methylation-mediated inhibition of UNC5 receptors and the associated clinical significance in CRC.MethodsMethylation and expression analysis was performed in TCGA datasets. And the results were confirmed in vitro in CRC cell lines treated with 5-aza-deoxycytidine. Then, the expression and epigenetic alterations of UNC5 receptors were evaluated in clinical specimens. Moreover, the diagnostic and prognostic values of the methylation alterations were also analyzed.ResultsMethylation-mediated repression was observed in UNC5C and UNC5D, but not in UNC5A and UNC5B, which was confirmed in CRC cell lines. Except for UNC5B, significantly elevated methylation was observed in UNC5A, UNC5C, and UNC5D in CRC. The discrimination efficiency of the three receptors was comparable with that of SEPT9. Kaplan–Meier curve survival analysis showed that hypermethylation of UNC5A, UNC5C and UNC5D was associated with poor progression-free and overall survival. Moreover, methylation levels of UNC5C and UNC5D were independent predictors of CRC progression-free (P = 0.001, P = 0.003, respectively) and overall survival (P = 0.008, P = 0.004, respectively).ConclusionsHypermethylation of UNC5C and UNC5D mediates the repression and has promising diagnostic and prognostic values in CRC.
Highlights
Colorectal cancer (CRC) accounts for nearly onetenth of all cancers and is the fourth leading cause of cancer-related death worldwide [1]
The potential of methylated UNC5C or UNC5D in circulating tumor DNA as biomarker for CRC should be taken into consideration in future study. In summary, this is the first study that comprehensively evaluates the aberrantly methylation of UNC5 receptors and the associated clinical significance in human colorectal cancer
Except for UNC5B, UNC5A, UNC5C and UNC5D were observed with significantly increased methylation levels in the promoter region
Summary
Colorectal cancer (CRC) accounts for nearly onetenth of all cancers and is the fourth leading cause of cancer-related death worldwide [1]. Deregulated DNA methylation is one of the hallmark events in colorectal carcinogenesis, characterized by global hypomethylation of the genome and paradoxical hypermethylation of CpG islands [2]. The former is thought to influence CRC development by inducing chromosomal instability, while the latter could result in transcriptional silencing of tumor suppressor genes [2]. Approaches for convenient and reliable detection of methylation with small amounts of DNA are available [5] These characteristics make DNA methylation as favorable CRC molecular marker with significant clinical value. Deregulated methylation of tumor suppressor genes is a hallmark event in colorectal cancer (CRC) carcinogenesis. We focused on the methylation-mediated inhibition of UNC5 receptors and the associated clinical significance in CRC
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