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.

Sirtuin 6 promotes transforming growth factor‐β1/H2O2/HOCl‐mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence

“…The Smad pathway was required for higher expression of SIRT6. These results are supported by published reports that c-Fos, which is activated by the ERK pathway, (22) could induce the expression of SIRT6, (23) and that Smad3 could cooperate with c-Fos in modulating gene expression. (24,25) Nevertheless, TGF-b1 alone could not induce higher expression of SIRT6 in HCC cells.…”

High Glucose Stimulates Tumorigenesis in Hepatocellular Carcinoma Cells Through AGER-Dependent O-GlcNAcylation of c-Jun

“…Furthermore, the c-Jun protein can be stabilized by both AGER and OGT. As the procarcinogenic role of c-Jun has been implicated in liver tumorigenesis (31,32), we suppose that hyperglycemia stimulates liver tumorigenesis maybe via O-GlcNAcylation and stabilization of c-Jun in an AGER/OGT-dependent manner. Increased AGER signaling has been demonstrated to promote signaling nodes including p38, ERK1/2, and nuclear factor-kB (33)(34)(35).…”

Analysis of expression profile data identifies key genes and pathways in hepatocellular carcinoma

“…The upregulation of c-FOS and Jun proto-oncogene mediated by protein kinase R promotes HCC proliferation (33). In addition, Fan et al (34) demonstrated that suppression of c-FOS, mediated by miR-139 downregulation, promotes HCC metastasis.…”