Methylation of the NEUROG1 gene is frequently found in sera of patients with colorectal cancers independent of tumor stage. The quantitative detection of NEUROG1 DNA methylation in serum is a suitable approach for the non-invasive screening for asymptomatic colorectal cancer.

Wnt/b-catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors. Under physiological conditions, b-catenin activity is tightly controlled. However, the majority of sporadic forms of colorectal cancer are characterized by inactivation of the tumor suppressor gene APC due to loss of heterozygosity (LOH), resulting in deregulation of the protein b-catenin. Apart from known b-catenin target genes like MYC, OPG, and DKK4, the gene TNFRSF19, a member of the TNF receptor superfamily, is regulated by b-catenin in mesenchymal stem cells (hMSC). We found that TNFRSF19 is frequently overexpressed in colorectal cancer cell lines and primary colorectal carcinomas. Further characterization revealed that both isoforms of TNFRSF19, TNFRSF19.1 and TNFRSF19.2, are regulated in a b-catenin dependent manner. The transcript TNFRSF19.2 encodes a 417 amino acid long protein containing a TRAF-binding site that links the TNFRSF19.2 to NF-jB signaling, whereas the isoform TNFRSF19.1 lacks this TRAF-binding site. Nevertheless both isoform 1 and 2 induced the activity of an NF-jB reporter gene. NF-jB signaling is important for inflammatory processes and chronic inflammatory diseases like ulcerative colitis and Crohn's disease, which are associated with increased risk for developing colorectal cancer. The observation that TNFRSF19 is a b-catenin target gene and TNFRSF19 receptor molecules activate NF-jB signaling shows that b-catenin regulates NF-jB activity via TNFRSF19, suggesting that TNFRSF19 may contribute to the development of colorectal tumors with deregulated b-catenin activity.

Colorectal cancer develops from adenomatous precursor lesions by a multistep process that involves several independent mutational events in oncogenes and tumor suppressor genes. Inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene is an early event and a prerequisite for the development of human colorectal adenoma. Previous in vitro studies identified DRO1 (CCDC80) to be a putative tumor suppressor gene that is negatively regulated in colorectal cancers and downregulated upon neoplastic transformation of epithelial cells. To investigate the in vivo role of DRO1 in colorectal carcinogenesis, a constitutive DRO1 knockout mouse model was generated. Disruption of DRO1 did not result in spontaneous intestinal tumor formation, consistent with the notion that DRO1 might have a role in suppressing the development of colon tumors in Apc Min/þ mice, a widely used model for studying the role of APC in intestinal tumorigenesis that is hampered by the fact that mice predominantly develop adenomas in the small intestine and not in the colon. Here, deletion of DRO1 in ApcMin/þ mice results in earlier death, a dramatically increased colonic tumor burden, and frequent development of colorectal carcinoma. Furthermore, enhanced phosphorylation of ERK1/2 is observed in colon epithelium and tumors from DRO1 knockout mice. Thus, this study reveals that inactivation of DRO1 is required for colorectal carcinogenesis in the Apc Min/þ mouse and establishes a new mouse model for the study of colorectal cancer.

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