title: DDX3 promotes tumor invasion in colorectal cancer via the CK1ε/Dvl2 axis.
abstract: DDX3, a subunit of CK1ε, phosphorylates Dvl2 to promote β-catenin activation. Overexpression of the Dvl2 protein results in potent activation of β-catenin/TCF signaling in colorectal cancer. Therefore, we hypothesized that DDX3 might promote tumor invasion via the CK1ε/Dvl2 axis due to β-catenin/TCF activation. Western blotting showed that β-catenin expression was decreased by DDX3 knockdown and increased by DDX3 overexpression in colorectal cancer cells. The TCF promoter activity and invasion capability were concomitantly increased and decreased by DDX3 manipulation in these cells. The invasion capability in colon cancer cells and xenograft lung tumor nodules induced by a DDX3-overexpressing T84 stable clone in tail-vein injection model were nearly suppressed by inhibitors of CK1ε (PF4800567) and β-catenin/TCF signaling (XAV939). Among colorectal cancer patients, DDX3 expression was positively correlated with the expression of pDvl2 and nuclear β-catenin in tumor tissues. The expression of pDvl2 occurred more frequently in high-nuclear than in low-nuclear β-catenin tumors. A prognostic significance of DDX3, pDvl2, and nuclear β-catenin on overall survival and relapse free survival was observed in this study population. We therefore suggest CK1ε or β-catenin/TCF signaling as potential targets for improving tumor regression and outcomes in colorectal cancer, particularly tumors with high-DDX3/high-nuclear β-catenin or high-DDX3/high-pDvl2/high-nuclear β-catenin expression.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Tsung-Ying
authors.initials: TY
authors.lastname: He
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: De-Wei
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Lin
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Lee
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Medicine, Chung Shan Medical University and Hospital, Taichung, Taiwan.|Department of Surgery, Chung Shan Medical University and Hospital, Taichung, Taiwan.
authors.forename: Chi-Chou
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.|School of Medicine, Chung Shan Medical University and Hospital, Taichung, Taiwan.|Department of Surgery, Chung Shan Medical University and Hospital, Taichung, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Chou
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
authors.forename: Huei
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D004195:Disease Models, Animal; D000072261:Dishevelled Proteins / Q000378:metabolism*; D005260:Female; D008297:Male; D009361:Neoplasm Invasiveness; D011379:Prognosis; D055550:Protein Stability; D059748:Proteolysis; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D051820:TCF Transcription Factors; D051176:beta Catenin; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases