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.
Highlights
Hepatitis C virus (HCV) is a leading cause of chronic liver disease and is a leading indication for liver transplantation [1]
Other recent reports indicate that protein kinase R (PKR) can directly stimulate cell growth through the p38 MAPK and NF-kB pathways [27,28]
The p38MAPK pathway is known to play a critical role in the pathogenesis of various malignancies [29,30], and NF-kB is known to regulate inflammatory cytokines, growth factors, angiogenic factors and anti-apoptotic effects, each of which can contribute to the process of carcinogenesis [31]
Summary
Hepatitis C virus (HCV) is a leading cause of chronic liver disease and is a leading indication for liver transplantation [1]. HCV establishes persistent infection and induces chronic hepatitis, which leads to liver cirrhosis (LC) and, frequently, to hepatocellular carcinoma (HCC) [2]. Of the many cellular proteins stimulated by HVC replication, double-stranded RNA-activated protein kinase R (PKR) appears to play a key antiviral role [3]. Double stranded-RNA produced by RNA viral replication is known to be a potent activator of PKR [4]. Activated PKR, in turn, induces PKR phosphorylation, and PKR dimerizes and phosphorylates eukaryotic initiation factor-2 alpha (eIF2a), which inhibits protein synthesis, including that of virally-encoded proteins [5]. PKR plays multiple roles in cell growth, differentiation, apoptosis, and responses to cellular stress occurring during RNA virus infections [6]
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