ROLE OF PROTEIN KINASE R IN INDUCING DNA DAMAGE IN HCV PATIENTS
Abstract
PKR is a p53 target gene and acts an imperative role in the tumor-suppressor role of p53. Initiation of p53 by genotoxic tension prompts a significant level of PKR expression, that ensuing in translational embarrassment and cell apoptosis. The current study aims to evaluate prognostic influence of PKR gene expression in chronic HCV patients; Correlate PKR and P53 gene expression to liver function tests and also shows the role of PKR in patients infected with HCV. We concluded that PKR was established to be an independent prognostic issue indicating the vital biological significance of this gene in the HCV disease process. In spite of the restriction of this study related to sample size, it paved the way for further future studies using more samples. Further investigations on a larger scale via well-standardized performances and more samples are recommended to validate these results of ROC curve or define a suitable one.
References
Agami R. and Bernards R. (2000). Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell J., 102:55-66,doi: 10.1016/s0092-8674(00)00010-6. PMID:10929713.
Chen G. G., Lai P. B., Ho R. L., Chan P. K., Xu H., Wong J. and Lau W. Y. (2004). Reduction of double-stranded RNA-activated protein kinase in hepatocellular carcinoma associated with hepatitis B virus. J. Med. Virol., 73:187-194. doi: 10.1002/jmv.20074.
Deb A., Zamanian-Daryoush M., Xu Z., Kadereit S. and Williams B. R. (2001). Protein kinase PKR is required for platelet-derived growth factor signalling of c-fos gene expression via Erks and Stat3. EMBO J., 20 (Suppl 10): 2487-2496.
De-Mitri M. S., Cassini R., Bagaglio S., Morsica G., Andreone P., Marino N. and Bernardi M. (2007). Evolution of hepatitis C virus non-structural 5A gene in the progression of liver disease to hepatocellular carcinoma. Liver Int., 27 (Suppl 8): 1126-1133.
El-dahshan D., Bahy D., Walid A., Ahmed A. E., Hanora A. (2018). Two novel SNPs in the promotor region of PKR gene in hepatitis C patients and their impact on disease outcome and response to treatment. Arab Journal of Gasteroenterology: The Official Publication of the Pan-Arab Association of Gastroenterology, 19: 106-115.
Gale M. and Foy E. M. (2005). Evasion of intracellular host defence by hepatitis C virus. Nature, 436 (7053): 939-945. doi: 10.1038/nature04078.
García M. A., Gil J., Ventoso I., Guerra S., Domingo E., Rivas C. and Esteban M. (2006). Impact of protein kinase PKR in cell biology: from antiviral to anti-proliferative action. Microbiology and molecular biology reviews: MMBR, 70 (Suppl 4): 1032-1060.
Hauri A. M., Armstrong G. L. and Hutin Y. J. (2004). The global burden of disease attributable to contaminated injections given in health care settings. Int. J. STD AIDS, 15: 7-16.
Hiasa Y., Kamegaya Y., Nuriya H., Onji M., Kohara M., Schmidt E. V. and Chung R. T. (2003). Protein kinase R is increased and is functional in hepatitis C virus-related hepatocellular carcinoma. Am. J. Gastroenterol., 98 (Suppl 11): 2528-2534.
Hung C. H., Chen C. H., Lee C. M., Wu C. M., Hu T. H., Wang J. H., Yen Y. H. and Lu S. N. (2008). Association of amino acid variations in the NS5A and E2- PePHD region of hepatitis C virus 1b with hepatocellular carcinoma. J. Viral. Hepatol., 15:58-65. doi: 10.1111/j.1365-2893.2007.00892.x.
Koike K. (2007). Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signalling pathways. J. Gastroenterol. Hepatol., 22 (Suppl 1): 108-111.
Kumar M., Zhao X. and Wang X. W. (2011). Molecular carcinogenesis of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: one step closer to personalized medicine. Cell Biosci., https://doi.org/10.1186/2045-3701-1-5
Loguercio C., A. Cuomo, Tuccillo C., Gazzerro P., Cioffi M., Molinari A., Del M. and Vecchio-Blanco C. (2003). Liver p53 expression in patients with HCV-related chronic hepatitis. J. Viral Hepat., 10:266- 270.
McPherson S., Powell E. E., Barrie H. D., Clouston A. D., McGuckin M. and Jonsson J. R. (2011). No evidence of unfolded protein response in patients with chronic hepatitis C virus infection. J. Gastroenterology hepatol., 26: 319-327.
Mitchell J. K., Midkiff B. R., Israelow B., Evans M. J., Lanford R. E., Walker C.M., Lemon S. M. and McGivern D. R. (2017). Hepatitis C virus indirectly disrupts DNA damage- induced p53 responses by activating protein kinase R. mBio. 8: e00121-17.https://doi.org/10.1128/mBio.00121-17
Mohamed A. A., Nada O. H. and El- Desouky M. A. (2012). Implication of protein kinase R gene quantification in hepatitis C virus genotype 4 induced hepatocarcenogenesis. Diagn. Pathol., 7: 103. https://doi.org/10.1186/1746-1596-7-103
Mohd H. K., Groeger J., Flaxman A. D. and Wiersma S. T. (2013). Global epidemiology of hepatitis C virus infection: new estimates of agespecific antibody to HCV seroprevalence. Hepatology, 57:1333-1342.
Onuki R., Bando Y., Suyama E., Katayama T., Kawasaki H., Baba T., Tohyama M. and Taira K. (2004). An RNA-dependent protein kinase is involved in tunicamycin induced apoptosis and Alzheimer’s disease. EMBO J., 23 (Suppl 4):959-968.
Tamada Y., Nakao K. and Nagayama Y. (2002). P48 Overexpression enhances interferon-mediated expression and activity of double- stranded RNA-dependent protein kinase in human hepatoma cells. J. Hepatol., 37 (Suppl 4): 493-499.
Terada T., Ueyama J., Ukita Y. and Ohta T. (2000). Protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers, fetal livers, primary biliary cirrhosis, hepatolithiasis and intrahepatic cholangiocarcinoma. Liver, 20 (Suppl 6): 450-457.
Toroney R., Nallagatla S. R., Boyer J. A., Cameron C. E. and Bevilacqua P. C. (2010). Regulation of PKR by HCV IRES RNA: importance of domain II and NS5A. J. Mol. Biol., 400 (Suppl 3): 393-412.
Yan X. B., Battaglia S., Boucreux D., Chen Z., Brechot C. and Pavio N. (2007). Mapping of the interacting domains of hepatitis C virus core protein and the double-stranded RNA-activated protein kinase (PKR). Virus Res., 125 (Suppl 1): 79-87.
