Mutated or dysregulated participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here, we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes, including ATF4-modulated genes in an aggressive OSCC cell line. DDX3 activated translation of and a set of its downstream targets, all of which contain upstream open reading frames (uORF). DDX3 promoted translation of these targets, likely by skipping the inhibitory uORF. DDX3 specifically enhanced the association of the cap-binding complex (CBC) with uORF-containing mRNAs and facilitated recruitment of the eukaryotic initiation factor 3 (eIF3). CBC and certain eIF3 subunits contributed to the expression of metastatic-related gene expression. Taken together, our results indicate a role for the novel DDX3-CBC-eIF3 translational complex in promoting metastasis. The discovery of DDX3-mediated expression of oncogenic uORF-containing genes expands knowledge on translational control mechanisms and provides potential targets for cancer therapy. http://cancerres.aacrjournals.org/content/canres/78/16/4512/F1.large.jpg .

The RNA-binding protein hnRNP Q has been implicated in neuronal mRNA metabolism. Here, we show that knockdown of hnRNP Q increased neurite complexity in cultured rat cortical neurons and induced filopodium formation in mouse neuroblastoma cells. Reexpression of hnRNP Q1 in hnRNP Q-depleted cells abrogated the morphological changes of neurites, indicating a specific role for hnRNP Q1 in neuronal morphogenesis. A search for mRNA targets of hnRNP Q1 identified functionally coherent sets of mRNAs encoding factors involved in cellular signaling or cytoskeletal regulation and determined its preferred binding sequences. We demonstrated that hnRNP Q1 bound to a set of identified mRNAs encoding the components of the actin nucleation-promoting Cdc42/N-WASP/Arp2/3 complex and was in part colocalized with Cdc42 mRNA in granules. Using subcellular fractionation and immunofluorescence, we showed that knockdown of hnRNP Q reduced the level of some of those mRNAs in neurites and redistributed their encoded proteins from neurite tips to soma to different extents. Overexpression of dominant negative mutants of Cdc42 or N-WASP compromised hnRNP Q depletion-induced neurite complexity. Together, our results suggest that hnRNP Q1 may participate in localization of mRNAs encoding Cdc42 signaling factors in neurites, and thereby may regulate actin dynamics and control neuronal morphogenesis.