DDX3 enhances oncogenic KRAS‑induced tumor invasion in colorectal cancer via the β‑catenin/ZEB1 axis
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De-Wei Wu1, Po-Lin Lin2, Ya-Wen Cheng1, Chi-Chou Huang3,4, Lee Wang5, Huei Lee1
1Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
2Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
3School of Medicine, Chung Shan Medical University, Taichung, Taiwan
4Department of Surgery, Division of Colon and Rectum, Chung Shan Medical University Hospital, Taichung, Taiwan
5School of Public Health, Chung Shan Medical University, Taichung, Taiwan
Huei Lee, e-mail: [email protected]
Keywords: DDX3, KRAS, β-catenin, AKT, colorectal cancer
Received: December 06, 2015 Accepted: February 21, 2016 Published: March 17, 2016
DDX3 plays a dual role in colorectal cancer; however, the role and underlying mechanism of DDX3 in colorectal tumorigenesis remains unclear. Here, we provide evidence that DDX3 enhances oncogenic KRAS transcription via an increase in SP1 binding to its promoter. Accelerating oncogenic KRAS expression by DDX3 promotes the invasion capability via the ERK/PTEN/AKT/β-catenin cascade. Moreover, the β-catenin/ZEB1 axis is responsible for DDX3-induced cell invasiveness and xenograft lung tumor nodule formation. The xenograft lung tumor nodules induced by DDX3-overexpressing T84 stable clone were nearly suppressed by the inhibitor of AKT (perifosine) or β-catenin (XAV939). Among patients, high KRAS, positive nuclear β-catenin expression and high ZEB1 were more commonly occurred in high-DDX3 tumors than in low-DDX3 tumors. High-DDX3, high-KRAS, positive nuclear β-catenin tumors, and high-ZEB1 exhibited worse overall survival (OS) and relapse free survival (RFS) than their counterparts. In conclusion, DDX3 may play an oncogenic role to promote tumor growth and invasion in colon cancer cells via the β-catenin/ZEB1 axis due to increasing KRAS transcription. We therefore suggest that AKT or β-catenin may potentially act as a therapeutic target to improve tumor regression and outcomes in colorectal cancer patients who harbored high-DDX3 tumors.
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