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DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked (DDX3X) is a member of the DEAD-box family of RNA helicases whose function has been revealed to be involved in RNA metabolism. Recent studies further indicate the abnormal expression in pan-cancers and the relevant biological effects on modulating cancer progression. However, <i>DDX3X</i>’s role in renal cell carcinoma (RCC) progression remains largely unknown. In this study, a medical informatics-based analysis using The Cancer Genome Atlas (TCGA) dataset was performed to evaluate clinical prognoses related to <i>DDX3X</i>. The results suggest that <i>DDX3X</i> is epigenetically repressed in tumor tissue and that lower <i>DDX3X</i> is correlated with the poor overall survival of RCC patients and high tumor size, lymph node metastasis, and distant metastasis (TNM staging system). Furthermore, knowledge-based transcriptomic analysis by Ingenuity Pathway Analysis (IPA) revealed that the SPINK1-metallothionein pathway is a top 1-repressed canonical signaling pathway by <i>DDX3X</i>. Furthermore, <i>SPINK1</i> and the metallothionein gene family all serve as poor prognostic indicators, and the expression levels of those genes are inversely correlated with <i>DDX3X</i> in RCC. Furthermore, digoxin was identified via Connectivity Map analysis (L1000) for its capability to reverse gene signatures in patients with low <i>DDX3X</i>. Importantly, cancer cell proliferation and migration were decreased upon digoxin treatment in RCC cells. The results of this study indicate the significance of the DDX3X_low/SPINK1_high/metallothionein_high axis for predicting poor survival outcome in RCC patients and suggest digoxin as a precise and personalized compound for curing those patients with low <i>DDX3X</i> expression levels.