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β‐catenin regulates NF‐κB activity via TNFRSF19 in colorectal cancer cells
Author(s) -
Schön Simon,
Flierman Isabelle,
Ofner Andrea,
Stahringer Anika,
Holdt Lesca Miriam,
Kolligs Frank T.,
Herbst Andreas
Publication year - 2014
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28839
Subject(s) - wnt signaling pathway , colorectal cancer , catenin , cancer research , biology , gene isoform , nf κb , deleted in colorectal cancer , beta catenin , mouse model of colorectal and intestinal cancer , signal transduction , cancer , gene , microbiology and biotechnology , genetics
Wnt/β‐catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors. Under physiological conditions, β‐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 β‐catenin. Apart from known β‐catenin target genes like MYC, OPG, and DKK4, the gene TNFRSF19, a member of the TNF receptor superfamily, is regulated by β‐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 β‐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‐κB signaling, whereas the isoform TNFRSF19.1 lacks this TRAF‐binding site. Nevertheless both isoform 1 and 2 induced the activity of an NF‐κB reporter gene. NF‐κB 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 β‐catenin target gene and TNFRSF19 receptor molecules activate NF‐κB signaling shows that β‐catenin regulates NF‐κB activity via TNFRSF19, suggesting that TNFRSF19 may contribute to the development of colorectal tumors with deregulated β‐catenin activity.