ZNRF3 acts as a tumour suppressor by the Wnt signalling pathway in human gastric adenocarcinoma
E3 ubiquitin ligases regulate a variety of biological processes through the ubiquitin–proteasome system, together with ubiquitin activating enzyme E1 and ubiquitin-conjugating enzyme E2. Previous studies have demonstrated that zinc and ring finger 3 (ZNRF3), which belongs to the E3 ubiquitin ligases family is involved in the Wnt signalling pathway, which plays an important role in causing cancer. However, the expression and function of ZNRF3 in human gastric adenocarcinoma still remains unclear. Immunohistochemical and western blot analysis showed a significant down-regulation of ZNRF3 protein in gastric adenocarcinoma tissues compared with adjacent normal gastric tissues. In addition, there was a correlation between the down-regulation of ZNRF3 and poor tissue differentiation in gastric adenocarcinoma. To investigate the potential function of ZNRF3 in cell proliferation and apoptosis, a gastric cell line SGC7901 was employed. The over-expression of wild-type ZNRF3, which was accomplished by the transient transfection of recombinant pEGFP-ZNRF3 (or empty plasmids as control) into the cell line SGC7901, was confirmed by western blot analysis. Flow-cytometry-based and Cell Counting Kit-8 assays showed that over-expression of wt ZNRF3 induced apoptosis and suppressed proliferation. ZNRF3-overexpressing gastric cells displayed partly attenuated protein levels of beta-catenin and TCF-4 compared with those transfected with the empty plasmid. Our study demonstrates a novel gastric adenocarcinoma suppressor and reveals that ZNRF3 inhibits gastric cancer cell growth and promotes the cell apoptosis by affecting the Wnt/beta-catenin/TCF signalling pathway.
KeywordsZNRF3 E3 ubiquitin ligases Gastric adenocarcinoma Wnt signalling Tumour suppressor
- Heo SH, Jeong ES, Lee KS, Seo JH, Jeong DG, Won YS, Kwon HJ, Kim HC, Kim DY, Choi YK (2012) Canonical Wnt signaling pathway plays an essential role in N-methyl-N-nitrosurea induced gastric tumorigenesis of mice. J Vet Med Sci [Epub ahead of print]Google Scholar
- Turing AM (1990) The chemical basis of morphogenesis. 1953. Bull Math Biol 52:153–197; discussion 119–152Google Scholar
- Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD, Eshleman JR, Goggins MG, Wolfgang CL, Canto MI et al (2011) Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci USA 108:21188–21193PubMedCrossRefGoogle Scholar