A Coiled-Coil Domain Containing 50 Splice Variant Is Modulated by Serine/Arginine-Rich Splicing Factor 3 and Promotes Hepatocellular Carcinoma in Mice by the Ras Signaling Pathway
Abstract
Deregulation of alternative splicing contributes to the malignant progression of cancer. Little is known about the significant alternative splicing events in hepatocellular carcinoma (HCC). High-throughput sequencing revealed that coiled-coil domain containing 50 (CCDC50) pre-mRNA is aberrantly spliced in 50% of our HCC cases. A BaseScope assay was performed to examine the expression of CCDC50S (a truncated oncogenic splice variant) in HCC tissues. Compared with benign liver tumors and several other types of solid tumors, CCDC50S mRNA was up-regulated in HCC, with a diagnostic potential (sensitivity, 0.711; specificity, 0.793). High expression of CCDC50S mRNA in HCC was significantly correlated with poor tumor differentiation, advanced tumor node metastasis (TNM) stage, and unfavorable prognosis. Overexpression of CCDC50S exerted tumorigenic activities that promoted HCC growth and metastasis by activation of Ras/forkhead box protein O4 (Foxo4) signaling. Either suppression of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation or overexpression of Foxo4 markedly attenuated CCDC50S-mediated phenotypes. Furthermore, serine- and arginine-rich splicing factor 3 (SRSF3) directly ...Continue Reading
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