Identification and Characterization of Ddx3 Downstream Epithelial-Mesenchymal Transition (Emt) Targets in Colorectal Cancer Metastasis

DEAD-box polypeptide 3 (DDX3) is a member of the DEAD-box family of RNA helicases, and its function has been reported to participate in pre-mRNA splicing, RNA export, transcription, and translation. In cancer, the complexity is further increased due to DEAD box proteins generally do not function alone but instead act as a component of multiprotein complexes, and both tumor promoting and tumor suppressing effects of DDX3 have been reported. We previously clarified the prognostic significance of DDX3 in patients of major cancer types through large cohort survival analysis and further investigated its effects on cancer progression. In large cohort survival analysis, DDX3 has a significant prognostic predictive power in colorectal cancer at both RNA and protein level. Patients with low DDX3 expression had poor prognosis and frequent distant metastasis. Our results further showed knockdown of DDX3 enhanced the migration and invasion in colon cancer cells and promoted tumor metastasis in vivo. Snail upregulation with decreased membranous E-cadherin expression and reduced cell aggregation were found after DDX3 silencing. However, the molecular mechanism is not clear. Hence, we hypothesize the DDX35s regulatory role in colon cancer epithelial-mesenchymal transition (EMT). DDX3 downstream EMT markers and RNA binding targets which repress colon cancer metastasis will be studied. We will further use Connectivity Map tool to identify the new use of old drugs. For this research goal, four Specific Aims have been established: Specific aim 1: To explore the mechanism of DDX3 -mediated Snail repression. Specific aim 2: To screen globally for DDX3 downstream EMT markers and signaling in metastasis. Specific aim 3: To identify and characterize DDX3 binding RNA regulating colon cancer metastasis. Specific aim 4: To screen drugs which induce DDX3 downstream signatures, and to evaluate the therapeutic efficacy of drug candidates on metastasis. This research project will identify novel EMT targets of DDX3 and provide fundamental knowledge for the future therapeutic strategies against colon cancer metastasis.