Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide; however, the molecular mechanisms regulating HCC progression remain largely unknown. In this study, we determined the role of DDX39 which a DEAD-box RNA helicase in HCC progression, and found DDX39 was upregulated in HCC tissues and cells, DDX39 expression was positive correlated with advanced clinical stage, survival analysis showed patients with high-DDX39 levels had poor outcome, it was an independent prognostic factor. Functional analysis revealed that DDX39 overexpression promoted HCC cell migration, invasion, growth, and metastasis, DDX39 knockdown inhibited HCC cell migration, invasion, growth, and metastasis. Mechanism analysis suggested DDX39 overexpression increased β-catenin expression in nucleus and increased Wnt/β-catenin pathway target genes levels, while DDX39 knockdown reduced this effect. Knockdown of Wnt/β-catenin pathway co-activators TCF4 and LEF1 in DDX39 overexpressing HCC cells inhibited Wnt/β-catenin pathway target genes. The invasion ability was also reduced, confirming DDX39 regulates HCC progression by activating Wnt/β-catenin pathway. In conclusion, we found DDX39 is a target and prognostic factor for HCC, and promotes HCC migration, invasion, growth, and metastasis by activating Wnt/β-catenin pathway.
Highlights
DDX39 is a DEAD box RNA helicase which unwind double-stranded RNA in an ATP-dependent manner, it interacts with Hepatocellular carcinoma (HCC)-1, U2AF65, REF2-1, TRF2, ALY, CIP29, and FUS/TLS to regulate transcription, splicing, RNA export, ribosome biogenesis, telomere protection and translation[1,2,3,4,5,6,7], DDX39 regulates tumor progression
To investigate the role of DDX39 in HCC progression, we first analyzed DDX39 expression in HCC tissues using data downloaded from GSE14520 which contains gene expression date of HCC, and found DDX39 was significantly upregulated in HCC tissues (Supplemental Fig. 1A)
We used TCGA date further to study DDX39 expression in HCC, and found DDX39 was significantly upregulated in HCC tissues compared to normal liver (Fig. 1a)
Summary
DDX39 is a DEAD box RNA helicase which unwind double-stranded RNA in an ATP-dependent manner, it interacts with HCC-1, U2AF65, REF2-1, TRF2, ALY, CIP29, and FUS/TLS to regulate transcription, splicing, RNA export, ribosome biogenesis, telomere protection and translation[1,2,3,4,5,6,7], DDX39 regulates tumor progression. DDX39 is overexpressed in lung squamous cell cancer, and promotes cancer cell proliferation[8]. DDX39 is an independent prognostic biomarker for gastrointestinal stromal tumor, and associated with metastasis[9]. Official journal of the Cell Death Differentiation Association. Zhang et al Cell Death and Disease (2018)9:675
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