Reduction of double‐stranded RNA‐activated protein kinase in hepatocellular carcinoma associated with hepatitis B virus

Chen, George G.; Lai, Paul B.S.; Ho, Raymond H.; Chan, Paul K.S.; Xu, Huaxi; Wong, John; Lau, Wan Yee

doi:10.1002/jmv.20074

Cited by 9 publications

(7 citation statements)

References 30 publications

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“…PKR activation is not sufficient to cause cell death because of the strong anti-apoptotic signalling in HCV infected cells [16]. Our work showed no significant difference in expression of PKR among patients with well differentiated tumours and those with poor or moderate differentiation, this is in concordance with other study [34]. While a previous report showed that the expression of PKR was increased significantly in well-differentiated HCC related HBV infection, compared with that in poorly differentiated HCC [36].…”

Section: Discussionsupporting

confidence: 92%

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Implication of protein kinase R Gene quantification in hepatitis C Virus Genotype 4 induced Hepatocarcinogenesis

2012

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BackgroundProtein kinase RNA (PKR-regulated) is a double-stranded RNA activated protein kinase whose expression is induced by interferon. The role of PKR in cell growth regulation is controversial, with some studies supporting a tumour suppressor function and others suggesting a growth-promoting role. However, it is possible that the function of PKR varies with the type of cancer in question.MethodsWe report here a detailed study to evaluate the function of PKR in hepatitis C virus genotype 4 (HCV-4) infected patients. PKR gene was quantitated in HCV related malignant and non-malignant liver tissue by RT-PCR technique and the association of HCV core and PKR was assessed.ResultsIf PKR functions as a tumour suppressor in this system, its expression would be higher in chronic hepatitis tissues. On the contrary our study demonstrated the specific association of HCV-4 with PKR expressed in hepatocellular carcinoma (HCC) tissues, leading to an increased gene expression of the kinase in comparison to chronic hepatitis tissues. This calls into question its role as a tumour suppressor and suggests a positive regulatory role of PKR in growth control of liver cancer cells. One limitation of most of other studies is that they measure the levels rather than the quantitation of PKR gene.ConclusionThe findings suggest that PKR exerts a positive role in cell growth control of HCV-4 related HCC, obtaining a cut-off value for PKR expression in liver tissue provides the first evidence for existence of a viral activator of PKR.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1267826959682402.

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Section: Discussionsupporting

confidence: 92%

“…Thus HCV core protein may induce a shift of PKR activity from its classical pathway by targeting other substrates [14,33]. Chen and his colleagues found that PKR level was much reduced in HCC than that in non-tumour tissues [34]. This is not surprising, as PKR is considered a tumour suppressor in some cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Implication of protein kinase R Gene quantification in hepatitis C Virus Genotype 4 induced Hepatocarcinogenesis

2012

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“…A good example might be that of Hepatitis B Virus (HBV) [36], [37], [38]. PKR expression was previously reported to be elevated in HCC liver from chronically HBV infected patients [39] and a relationship between PKR and IFN induction during HBV infection would be important to evaluate.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response

et al. 2011

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Recognition of viral RNA structures by the intracytosolic RNA helicase RIG-I triggers induction of innate immunity. Efficient induction requires RIG-I ubiquitination by the E3 ligase TRIM25, its interaction with the mitochondria-bound MAVS protein, recruitment of TRAF3, IRF3- and NF-κB-kinases and transcription of Interferon (IFN). In addition, IRF3 alone induces some of the Interferon-Stimulated Genes (ISGs), referred to as early ISGs. Infection of hepatocytes with Hepatitis C virus (HCV) results in poor production of IFN despite recognition of the viral RNA by RIG-I but can lead to induction of early ISGs. HCV was shown to inhibit IFN production by cleaving MAVS through its NS3/4A protease and by controlling cellular translation through activation of PKR, an eIF2α-kinase containing dsRNA-binding domains (DRBD). Here, we have identified a third mode of control of IFN induction by HCV. Using HCVcc and the Huh7.25.CD81 cells, we found that HCV controls RIG-I ubiquitination through the di-ubiquitine-like protein ISG15, one of the early ISGs. A transcriptome analysis performed on Huh7.25.CD81 cells silenced or not for PKR and infected with JFH1 revealed that HCV infection leads to induction of 49 PKR-dependent genes, including ISG15 and several early ISGs. Silencing experiments revealed that this novel PKR-dependent pathway involves MAVS, TRAF3 and IRF3 but not RIG-I, and that it does not induce IFN. Use of PKR inhibitors showed that this pathway requires the DRBD but not the kinase activity of PKR. We then demonstrated that PKR interacts with HCV RNA and MAVS prior to RIG-I. In conclusion, HCV recruits PKR early in infection as a sensor to trigger induction of several IRF3-dependent genes. Among those, ISG15 acts to negatively control the RIG-I/MAVS pathway, at the level of RIG-I ubiquitination.These data give novel insights in the machinery involved in the early events of innate immune response.

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“…In addition to interferon-inducible genes with antiviral activity, several genes known or predicted to possess growth-inhibition and/or cell-differentiating activities [49,50] were induced by imiquimod, including IFI16 , AIM2 [62,63], IFIH1 (melanoma differentiation antigen, MDA5 ) [45], CXCL10 ( IP10 ) [58] and EIF2AK2 (PRKR ) [64]. Some of the interferon-inducible genes also possess pro-apoptotic activity, including MX1 , TNFSF10 ( TRAIL ), OAS1 , and PRF1 [55,57,65].…”

Section: Resultsmentioning

confidence: 99%

Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream

et al. 2007

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BackgroundThe objective of this study was to identify the molecular processes responsible for the anti-lesional activity of imiquimod in subjects with actinic keratosis using global gene expression profiling.MethodsA double-blind, placebo-controlled, randomized study was conducted to evaluate gene expression changes in actinic keratosis treated with imiquimod 5% cream. Male subjects (N = 17) with ≥ 5 actinic keratosis on the scalp applied placebo cream or imiquimod 3 times a week on nonconsecutive days for 4 weeks. To elucidate the molecular processes involved in actinic keratosis lesion regression by imiquimod, gene expression analysis using oligonucleotide arrays and real time reverse transcriptase polymerase chain reaction were performed on shave biopsies of lesions taken before and after treatment.ResultsImiquimod modulated the expression of a large number of genes important in both the innate and adaptive immune response, including increased expression of interferon-inducible genes with known antiviral, anti-proliferative and immune modulatory activity, as well as various Toll-like receptors. In addition, imiquimod increased the expression of genes associated with activation of macrophages, dendritic cells, cytotoxic T cells, and natural killer cells, as well as activation of apoptotic pathways.ConclusionData suggest that topical application of imiquimod stimulates cells in the skin to secrete cytokines and chemokines that lead to inflammatory cell influx into the lesions and subsequent apoptotic and immune cell-mediated destruction of lesions.

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Reduction of double‐stranded RNA‐activated protein kinase in hepatocellular carcinoma associated with hepatitis B virus

Cited by 9 publications

References 30 publications

Implication of protein kinase R Gene quantification in hepatitis C Virus Genotype 4 induced Hepatocarcinogenesis

Implication of protein kinase R Gene quantification in hepatitis C Virus Genotype 4 induced Hepatocarcinogenesis

Hepatitis C Virus Reveals a Novel Early Control in Acute Immune Response

Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream

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