Nuclear DDX3 expression predicts poor outcome in colorectal and breast cancer

Abstract

PurposeDEAD box protein 3 (DDX3) is an RNA helicase with oncogenic properties that shuttles between the cytoplasm and nucleus. The majority of DDX3 is found in the cytoplasm, but a subset of tumors has distinct nuclear DDX3 localization of yet unknown biological significance. This study aimed to evaluate the significance of and mechanisms behind nuclear DDX3 expression in colorectal and breast cancer.MethodsExpression of nuclear DDX3 and the nuclear exporter chromosome region maintenance 1 (CRM1) was evaluated by immunohistochemistry in 304 colorectal and 292 breast cancer patient samples. Correlations between the subcellular localization of DDX3 and CRM1 and the difference in overall survival between patients with and without nuclear DDX3 were studied. In addition, DDX3 mutants were created for in vitro evaluation of the mechanism behind nuclear retention of DDX3.ResultsDDX3 was present in the nucleus of 35% of colorectal and 48% of breast cancer patient samples and was particularly strong in the nucleolus. Nuclear DDX3 correlated with worse overall survival in both colorectal (hazard ratio [HR] 2.34, P<0.001) and breast cancer (HR 2.39, P=0.004) patients. Colorectal cancers with nuclear DDX3 expression more often had cytoplasmic expression of the nuclear exporter CRM1 (relative risk 1.67, P=0.04). In vitro analysis of DDX3 deletion mutants demonstrated that CRM1-mediated export was most dependent on the N-terminal nuclear export signal.ConclusionOverall, we conclude that nuclear DDX3 is partially CRM1-mediated and predicts worse survival in colorectal and breast cancer patients, putting it forward as a target for therapeutic intervention with DDX3 inhibitors under development in these cancer types.

DDX3X Multifunctionally Modulates Tumor Progression and Serves as a Prognostic Indicator to Predict Cancer Outcomes

“…Similar observations were uncovered in another breast cancer cohort study, in which 35% of the breast cancer patients displayed high DDX3X levels that correlated with poor clinical outcomes [28]. Furthermore, the prognostic power of DDX3X has been specifically correlated with the nuclear DDX3X expression level in both breast and colorectal cancers [29]. In head and neck squamous cell carcinoma patients, the DDX3X level correlates with lymph node metastasis and a poor prognosis [30].…”

The TRPV4 channel links calcium influx to DDX3X activity and viral infectivity

“…Our study reveals that an ion channel, particularly well suited to sense the environment confers an additional regulatory layer in the tuning of RNA metabolism to changing environments. Altogether, our data propose TRPV4 as an interesting target to explore as therapeutic intervention in both DDX3X-dependent viral infections 55 and cancers in which DDX3X nuclear accumulation is associated to poor prognosis 56 .…”

A Computational Approach with Biological Evaluation: Combinatorial Treatment of Curcumin and Exemestane Synergistically Regulates DDX3 Expression in Cancer Cell Lines

“…DEAD box protein 3, DDX3, also referred to as DDX3X, belongs to the family of DEAD box RNA helicase [ 1 ]. These RNA helicases demonstrate a specific motif called the DEAD/H (Asp-Glu-Ala-Asp/His) [ 2 ].…”

“…In humans, there exists at least two pseudo genes and two DDX3 homologs, DDX3X and DDX3Y, sharing about 92% of protein sequence identity with varied functional and expression patters across various organs [ 2 ]. Notably, the protein is known to transport between cytoplasm and nucleus [ 1 , 5 ], however is primarily localized in cytoplasm in a majority of human tissues and cell lines [ 1 ]. DDX3 is positioned on the X-chromosome bands p11.3 --> p11.23 [ 2 , 6 ] whose deletion is embryonically lethal.…”