Format

Send to

Choose Destination
Cancers (Basel). 2019 Sep 20;11(10). pii: E1407. doi: 10.3390/cancers11101407.

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

Author information

1
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. yaydin@tulane.edu.
2
Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. rkurt@tulane.edu.
3
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. ksong@tulane.edu.
4
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. dlin6@tulane.edu.
5
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. hosman1@tulane.edu.
6
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. byoungquist@tulane.edu.
7
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. jscottmd@tulane.edu.
8
Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. shoresnj@gmail.com.
9
Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA. paul.thevenot@oschner.org.
10
Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA. acohen@oschner.org.
11
Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. sdash@tulane.edu.
12
Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. sdash@tulane.edu.

Abstract

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.

KEYWORDS:

cirrhosis; endoplasmic reticulum (ER) stress; hepatitis C virus (HCV); hepatocellular carcinoma (HCC); hepatocyte nuclear factor 4 alpha (HNF4A); microRNA-122 (miR-122); nuclear factor erythroid 2-related factor 2 (NRF2); oxidative stress (OS); signal transducer and activator of transcription 3 (STAT3); unfolded protein response (UPR)

PMID:
31547152
DOI:
10.3390/cancers11101407
Free full text

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI)
Loading ...
Support Center