Novel role of STRAP in progression and metastasis of colorectal cancer through Wnt/β-catenin signaling
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Guandou Yuan1,3, Bixiang Zhang3, Shanzhong Yang1, Lin Jin1, Arunima Datta1, Sejong Bae4, Xiaoping Chen3, Pran K Datta1,2
1Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
2Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
3Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
4Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
Pran K Datta, e-mail: firstname.lastname@example.org
Xiaoping Chen, e-mail: email@example.com
Keywords: STRAP, β-catenin, CRC, metastasis, tissue microarray
Received: October 23, 2015 Accepted: January 29, 2016 Published: February 20, 2016
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.
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