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Open AccessArticle

Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression

1
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
2
Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
3
Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1407; https://doi.org/10.3390/cancers11101407
Received: 20 August 2019 / Revised: 14 September 2019 / Accepted: 16 September 2019 / Published: 20 September 2019
(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)
Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection. View Full-Text
Keywords: hepatitis C virus (HCV); cirrhosis; hepatocellular carcinoma (HCC); endoplasmic reticulum (ER) stress; oxidative stress (OS); unfolded protein response (UPR); microRNA-122 (miR-122); nuclear factor erythroid 2-related factor 2 (NRF2); signal transducer and activator of transcription 3 (STAT3); hepatocyte nuclear factor 4 alpha (HNF4A) hepatitis C virus (HCV); cirrhosis; hepatocellular carcinoma (HCC); endoplasmic reticulum (ER) stress; oxidative stress (OS); unfolded protein response (UPR); microRNA-122 (miR-122); nuclear factor erythroid 2-related factor 2 (NRF2); signal transducer and activator of transcription 3 (STAT3); hepatocyte nuclear factor 4 alpha (HNF4A)
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Aydin, Y.; Kurt, R.; Song, K.; Lin, D.; Osman, H.; Youngquist, B.; Scott, J.W.; Shores, N.J.; Thevenot, P.; Cohen, A.; Dash, S. Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression. Cancers 2019, 11, 1407.

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