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DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control

Oncogene volume 25, pages 1991–2003 (2006)Cite this article

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and is highly correlated with hepatitis virus infection. Our previous report shows that a DEAD box RNA helicase, DDX3, is targeted and regulated by hepatitis C virus (HCV) core protein, which implicates the involvement of DDX3 in HCV-related HCC development. In this study, the potential role of DDX3 in hepatocarcinogenesis is investigated by examining its expression in surgically excised human HCC specimens. Here we report the differential deregulation of DDX3 expression in hepatitis virus-associated HCC. A significant downregulation of DDX3 expression is found in HCCs from hepatitis B virus (HBV)-positive patients, but not from HCV-positive ones, compared to the corresponding nontumor tissues. The expression of DDX3 is differentially regulated by the gender and, moreover, there is a tendency that the downregulation of DDX3 expression in HCCs is more frequent in males than in females. Genetic knockdown of DDX3 with small interfering RNAs (siRNA) in a nontransformed mouse fibroblast cell line, NIH-3T3, results in a premature entry to S phase and an enhancement of cell growth. This enhanced cell cycle progression is linked to the upregulation of cyclin D1 and the downregulation of p21WAF1 in the DDX3 knockdown cells. In addition, constitutive reduction of DDX3 expression increases the resistance of NIH-3T3 cells to serum depletion-induced apoptosis and enhances the ras-induced anchorage-independent growth, indicating the involvement of DDX3 in cell growth control. These findings together with the previous study suggest that the deregulation of DDX3, a DEAD box RNA helicase with cell growth-regulatory functions, is involved in HBV- and HCV-associated pathogenesis.

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Acknowledgements

We thank Dr Kou-Juey Wu of the Institute of Biochemistry and Molecular Biology, National Yang-Ming University for providing the plasmid pSuper and pMT2T-wt-myc, and Dr Hsin-Fang Yang-Yen of the Institute of Molecular Biology, Academia Sinica for providing the plasmid pZIP-viral-H-ras. We are also grateful to Dr R Kirby for critical reading and comments on this manuscript. This work was supported by grants from the National Science Council (NSC-91-2320-B-010-072MH, NSC-92-2320-B -010-014MH and NSC-93-2320-B-010-049MH) and the National Health Research Institute (NHRI-EX91-9002BL, NHRI-EX92-9002BL, NHRI-EX93-9002BL and NHRI-EX94-9002BL) to Dr YHW Lee.

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Authors and Affiliations

  1. Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China

    P-C Chang, Y-H Tsai & Y-H Wu Lee

  2. Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, Republic of China

    C-W Chi

  3. Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China

    G-Y Chau

  4. Department of Pathology, National Yang-Ming University, Taipei, Taiwan, Republic of China

    F-Y Li

  5. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China

    J-C Wu

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Correspondence to Y-H Wu Lee.

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Chang, PC., Chi, CW., Chau, GY. et al. DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control. Oncogene 25, 1991–2003 (2006). https://doi.org/10.1038/sj.onc.1209239

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