Novel role of STRAP in progression and metastasis of colorectal cancer through Wnt/β-catenin signaling

Abstract

// Guandou Yuan 1, 3 , Bixiang Zhang 3 , Shanzhong Yang 1 , Lin Jin 1 , Arunima Datta 1 , Sejong Bae 4 , Xiaoping Chen 3 , Pran K Datta 1, 2 1 Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA 2 Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA 3 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 4 Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to: Pran K Datta, e-mail: prandatta@uabmc.edu Xiaoping Chen, e-mail: chenxpchenxp@163.com Keywords: STRAP, β-catenin, CRC, metastasis, tissue microarray Received: October 23, 2015      Accepted: January 29, 2016      Published: February 20, 2016 ABSTRACT Serine-Threonine Kinase Receptor-Associated Protein (STRAP) interacts with a variety of proteins and influences a wide range of cellular processes. Aberrant activation of Wnt/β-catenin signaling has been implicated in the development of colorectal cancer (CRC). Here, we show the molecular mechanism by which STRAP induces CRC metastasis by promoting β-catenin signaling through its stabilization. We have genetically engineered a series of murine and human CRC and lung cancer cell lines to investigate the effects of STRAP on cell migration and invasion in vitro , and on tumorigenicity and metastasis in vivo . Downregulation of STRAP inhibits invasion, tumorigenicity, and metastasis of CRC cells. Mechanistically, STRAP binds with GSK-3β and reduces the phosphorylation, ubiquitylation, and degradation of β-catenin through preventing its binding to the destruction complex. This leads to an inhibition of Wnt/β-catenin signaling and reduction in the expression of downstream targets, such as Cyclin D1, matrix metalloproteinases 2 and 9, and ß-TrCP. In human CRC specimens, higher STRAP expression correlates significantly with β-catenin expression with increased nuclear levels ( R =0.696, p < .0001, n =128). Together, these results suggest that STRAP increases invasion and metastasis of CRC partly through inhibiting ubiquitin-dependent degradation of β-catenin and promoting Wnt/β-catenin signaling.