title: DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control.
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 p21(WAF1) 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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: P-C
authors.initials: PC
authors.lastname: Chang
authors.forename: C-W
authors.initials: CW
authors.lastname: Chi
authors.forename: G-Y
authors.initials: GY
authors.lastname: Chau
authors.forename: F-Y
authors.initials: FY
authors.lastname: Li
authors.forename: Y-H
authors.initials: YH
authors.lastname: Tsai
authors.forename: J-C
authors.initials: JC
authors.lastname: Wu
authors.forename: Y-H
authors.initials: YH
authors.lastname: Wu Lee
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002455:Cell Division / Q000502:physiology*; D053487:DEAD-box RNA Helicases; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus / Q000472:pathogenicity*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000821:virology; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D020365:RNA Helicases / Q000235:genetics* / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
chemical_list: D034741:RNA, Small Interfering; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases