title: Protein kinase R modulates c-Fos and c-Jun signaling to promote proliferation of hepatocellular carcinoma with hepatitis C virus infection.
abstract: Double-stranded RNA-activated protein kinase R (PKR) is known to be upregulated by hepatitis C virus (HCV) and overexpressed in hepatocellular carcinoma (HCC). However, the precise roles of PKR in HCC with HCV infection remain unclear. Two HCV replicating cell lines (JFH-1 and H77s), generated by transfection of Huh7.5.1 cells, were used for experiments reported here. PKR expression was modulated with siRNA and a PKR expression plasmid, and cancer-related genes were assessed by real-time PCR and Western blotting; cell lines were further analyzed using a proliferation assay. Modulation of genes by PKR was also assessed in 34 human HCC specimens. Parallel changes in c-Fos and c-Jun gene expression with PKR were observed. Levels of phosphorylated c-Fos and c-Jun were upregulated by an increase of PKR, and were related to levels of phosphorylated JNK1 and Erk1/2. DNA binding activities of c-Fos and c-Jun also correlated with PKR expression, and cell proliferation was dependent on PKR-modulated c-Fos and c-Jun expression. Coordinate expression of c-Jun and PKR was confirmed in human HCC specimens with HCV infection. PKR upregulated c-Fos and c-Jun activities through activation of Erk1/2 and JNK1, respectively. These modulations resulted in HCC cell proliferation with HCV infection. These findings suggest that PKR-related proliferation pathways could be an attractive therapeutic target.
authors.affiliation: Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hiasa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Tokumoto
authors.forename: Masashi
authors.initials: M
authors.lastname: Hirooka
authors.forename: Masanori
authors.initials: M
authors.lastname: Abe
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Bunzo
authors.initials: B
authors.lastname: Matsuura
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.forename: Morikazu
authors.initials: M
authors.lastname: Onji
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016174:Hepacivirus / Q000502:physiology; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D019892:eIF-2 Kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3