β-catenin regulates NF-κB activityviaTNFRSF19 in colorectal cancer cells

Abstract

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.

TROY is a promising prognostic biomarker in patients with colorectal cancer

“…Regarding the prognostic significance of TROY, one research group reported no increase in TROY mRNA in CRC specimens in a small sample of patients (n=20) (13). In contrast, another group reported an increase in TROY mRNA expression in 4 of 8 CRC tissues but did not investigate its prognostic significance (17). Because the number of samples analyzed in both reports was small, they were insufficient to evaluate the prognostic significance of the expression level of TROY.…”

“…One research group reported that TROY is significantly up-regulated in neoplastic tissues from mice during intestinal tumorigenesis and is produced specifically by fast-cycling intestinal stem cells (13). Another research group suggested that TROY can contribute to the initiation or progression of colorectal tumors with deregulated β-catenin activity (17). Regarding the prognostic significance of TROY, one research group reported no increase in TROY mRNA in CRC specimens in a small sample of patients (n=20) (13).…”

“…Recently, TROY was reported to be a β-catenin target gene and to form a complex with LGR5 in cellular membranes (13). Although overexpression of TROY is observed in CRC cell lines (14)(15)(16)(17), its clinical significance for CRC is poorly understood. Because TROY might be a possible prognostic biomarker of CRC, we performed this study to investigate the clinical significance of TROY in patients with CRC and compared its clinical usefulness to that of LGR5.…”

Ellagic acid regulates Wnt/β-catenin signaling pathway and CDK8 in HCT 116 and HT 29 colon cancer cells

“…Since Wnt/ -catenin signaling plays a critical role in the regulation of colon tissue regeneration and the development of colon cancer (Schon et al, 2014), the expression of Wnt/ -catenin signaling proteins were assessed after exposure to ellagic acid. The expression of -catenin was decreased significantly in HT29 and in HCT 116 cells treated with ellagic acid, however a marked increase in the expression of p--catenin levels was observed.…”

“…Colon cancer carcinogenesis has been reported to be associated with genetic errors in genes involved in apoptosis and cell proliferation (Davies et al, 2005;Watson, 2006;Damaschke et al, 2013;Bharati et al, 2014). Genetic defects triggering aberrant activation of Wnt/ -catenin signalling are common and are reported in over 90% of sporadic cases of colon cancer (Miyaki et al, 1994;Clevers, 2006;Klaus and Birchmeier, 2008;Schon et al, 2014). The key effecttor of Wnt/ -catenin signaling pathway is -catenin that upon activation of Wnt signal, translocates into the nuclear region forming a ternary complex with transcription factors-TCF/Lef (T-cell factor, lymphoid enhancer factor) and activates genes involved in cell pro- Studies have demonstrated that phytochemicals are effective in modulating Wnt/ -catenin signalling pathway (Zhang, et al, 2013;Kim et al, 2014).…”