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Sci Rep. 2017 Aug 23;7(1):9223. doi: 10.1038/s41598-017-10087-6.

Activation of PERK-Nrf2 oncogenic signaling promotes Mdm2-mediated Rb degradation in persistently infected HCV culture.

Author information

1
Department of Medicine, Division of Gastroenterology and Hepatology, New Orleans, Louisiana, USA.
2
Department of Pathology and Laboratory Medicine, New Orleans, Louisiana, USA.
3
Department of Medicinal Chemistry, College of Pharmacy, University of Utah, Salt Lake City, UT, USA.
4
Department of Medicine and Genetics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
5
Laboratory of Transplantation Surgery and Regenerative Medicine, University of Gothenburg, Gothenburg, Sweden.
6
School of Medicine, LSU Health Sciences Center, New Orleans, Louisiana, USA.
7
Department of Biochemistry, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
8
Department of Pathology and Laboratory Medicine, New Orleans, Louisiana, USA. sdash@tulane.edu.
9
Department of Medicine, Division of Gastroenterology and Hepatology, New Orleans, Louisiana, USA. sdash@tulane.edu.

Abstract

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.

PMID:
28835697
PMCID:
PMC5569052
DOI:
10.1038/s41598-017-10087-6
[Indexed for MEDLINE]
Free PMC Article

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