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.

A double-edged function of DDX3, as an oncogene or tumor suppressor, in cancer progression (Review)

“…In contrast, several groups obtain different conclusions of the role of DDX3 in colorectal cancer (37)(38)(39)(40). In KRAS-mutated colon cancer cells, DDX3 promotes cell invasion and the nodule formation of xenograft lung tumor due to β-catenin/TCF activation through the CK1ε/Dvl2 axis (37). In addition, DDX3 enhances KRAS transcription and activates the following β-catenin/ZEB1 signaling to promote KRAS-mediated tumor invasion (38).…”

“…Inhibition of DDX3 by a small inhibitor RK-33 reduces cell proliferation and causes a G1 arrest in colorectal cancer cells (40). In addition, a high DDX3 expression leads to poor clinical overall survival (OS) for colorectal cancer patients (37)(38)(39)(40).…”

“…DDX3 directly binds to CK1ε to stimulate its kinase activity, and further promotes phosphorylation of the scaffold protein dishevelled (Dvl), thus facilitating β-catenin translocation into nucleus in a Wnt-dependent manner during the development of mammalian cells (55). Similarly, DDX3 acts as a subunit of CK1ε and phosphorylates Dvl2 to activate β-catenin/TCF signaling, and finally enhances tumor invasion in colorectal cancer (37). In addition, DDX3 increases protein levels of both Rac1 and β-catenin, and thereby promotes Wnt signaling to modulate cell adhesion, migration and metastasis (56).…”

“…DDX3 interacts with variable proteins to involve in different signaling pathways, which also determines its function as tumor suppression or oncogenic role in cancer progression. For example, DDX3 exerts tumor suppression potentials by downregulating Snail in colorectal cancer DLD-1 and HCT116 cells, while it interacts with CK1ε to activate β-catenin/TCF signaling to promote cancer progress in colorectal cancer cells (37,47). It is likely more reasonable to jointly consider multiple DDX3-associated proteins to analyze their influences on tumors and the patients OS.…”

The YAP1/SIX2 axis is required for DDX3-mediated tumor aggressiveness and cetuximab resistance in KRAS-wild-type colorectal cancer

“…We recently reported that DDX3 promoted tumor invasion in colorectal cancer, regardless of APC loss, by activating β-catenin/TCF signaling via the CK1ε/Dvl2 axis 10. We further demonstrated that DDX3 upregulated KRAS transcription and enhanced oncogenic KRAS-mediated tumor invasion following β-catenin/TCF activation by MEK/ERK and PI3K/AKT signaling 11.…”