| Background:Serine-Threonine Kinase Receptor-Associated Protein (STRAP) is a WD40 domain protein, which endows it with capability to interact with a variety of proteins and influence a wide range of cellular processes. Aberrant activation of Wnt/?-catenin signaling has been implicated in the development of various malignancies, including Colorectal Cancer (CRC). In this study, we investigated the mechanism and biological outcome of STRAP mediated stabilization of ?-catenin in CRC.Methods:We investigated the effects of knockdown of STRAP in CRC cell lines on cell growth, migration and invasion in vitro; tumorigenicity and metastasis in orthotopic cecum injection and splenic injection model. We also detected the expression of STRAP and ?-catenin in 128 colorectal cancers using immunohistochemistry.Results:Downregulation of STRAP inhibited tumorigenicity and metastasis. Mechanistically, we found that knockdown of STRAP led to degradation of ?-catenin, inhibition of Wnt/?-catenin signaling transcription activity and decrease of the expression of its downstream target genes cyclinD1 and matrix metalloproteinase 2 and 9, whereas relative phosphorylation of P-catenin at Ser33/37/Thr41, which initiate ?-catenin ubiquitin-dependent degradation, was up-regulated. Furthermore, we noted that over expression of STRAP significantly reduced binding of ?-catenin into the destruction complex and inhibited its subsequent ubiquitylation. In human CRC samples, we found that both STRAP and ?-catenin were up-regulated and highly significant correlation between these two proteins was observed using Spearman coefficient rank correlation analysis (r=0.647,p<.0001, n=128).Conclusions:STRAP modulates Wnt/?-catenin signaling through inhibiting ?-catenin ubiquitin-dependent degradation. The newly identified oncogenic function of STRAP provides new insight into the progression of CRC. Further study of STRAP may provide valuable therapeutic targets for CRC. |
PDF Full Text Request