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Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture
The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569052/ https://www.ncbi.nlm.nih.gov/pubmed/28835697 http://dx.doi.org/10.1038/s41598-017-10087-6 |
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author | Aydin, Yucel Chedid, Milad Chava, Srinivas Danielle Williams, Donkita Liu, Shuanghu Hagedorn, Curt H. Sumitran-Holgersson, Suchitra Reiss, Krzysztof Moroz, Krzysztof Lu, Hua Balart, Luis A. Dash, Srikanta |
author_facet | Aydin, Yucel Chedid, Milad Chava, Srinivas Danielle Williams, Donkita Liu, Shuanghu Hagedorn, Curt H. Sumitran-Holgersson, Suchitra Reiss, Krzysztof Moroz, Krzysztof Lu, Hua Balart, Luis A. Dash, Srikanta |
author_sort | Aydin, Yucel |
collection | PubMed |
description | The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation. |
format | Online Article Text |
id | pubmed-5569052 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-55690522017-09-01 Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture Aydin, Yucel Chedid, Milad Chava, Srinivas Danielle Williams, Donkita Liu, Shuanghu Hagedorn, Curt H. Sumitran-Holgersson, Suchitra Reiss, Krzysztof Moroz, Krzysztof Lu, Hua Balart, Luis A. Dash, Srikanta Sci Rep Article The mechanism of how chronic hepatitis C virus (HCV) infection leads to such a high rate of hepatocellular carcinoma (HCC) is unknown. We found that the PERK axis of endoplasmic reticulum (ER) stress elicited prominent nuclear translocation of Nrf2 in 100% of HCV infected hepatocytes. The sustained nuclear translocation of Nrf2 in chronically infected culture induces Mdm2-mediated retinoblastoma protein (Rb) degradation. Silencing PERK and Nrf2 restored Mdm2-mediated Rb degradation, suggesting that sustained activation of PERK/Nrf2 axis creates oncogenic stress in chronically infected HCV culture model. The activation of Nrf2 and its nuclear translocation were prevented by ER-stress and PERK inhibitors, suggesting that PERK axis is involved in the sustained activation of Nrf2 signaling during chronic HCV infection. Furthermore, we show that HCV clearance induced by interferon-α based antiviral normalized the ER-stress response and prevented nuclear translocation of Nrf2, whereas HCV clearance by DAAs combination does neither. In conclusion, we report here a novel mechanism for how sustained activation of PERK axis of ER-stress during chronic HCV infection activates oncogenic Nrf2 signaling that promotes hepatocyte survival and oncogenesis by inducing Mdm2-mediated Rb degradation. Nature Publishing Group UK 2017-08-23 /pmc/articles/PMC5569052/ /pubmed/28835697 http://dx.doi.org/10.1038/s41598-017-10087-6 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Aydin, Yucel Chedid, Milad Chava, Srinivas Danielle Williams, Donkita Liu, Shuanghu Hagedorn, Curt H. Sumitran-Holgersson, Suchitra Reiss, Krzysztof Moroz, Krzysztof Lu, Hua Balart, Luis A. Dash, Srikanta Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture |
title | Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture |
title_full | Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture |
title_fullStr | Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture |
title_full_unstemmed | Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture |
title_short | Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture |
title_sort | activation of perk-nrf2 oncogenic signaling promotes mdm2-mediated rb degradation in persistently infected hcv culture |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5569052/ https://www.ncbi.nlm.nih.gov/pubmed/28835697 http://dx.doi.org/10.1038/s41598-017-10087-6 |
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