PMID- 31547152 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200930 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 11 IP - 10 DP - 2019 Sep 20 TI - Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression. LID - 10.3390/cancers11101407 [doi] LID - 1407 AB - 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. FAU - Aydin, Yucel AU - Aydin Y AUID- ORCID: 0000-0001-6727-6296 AD - Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. yaydin@tulane.edu. FAU - Kurt, Ramazan AU - Kurt R AD - Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. rkurt@tulane.edu. FAU - Song, Kyoungsub AU - Song K AD - Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. ksong@tulane.edu. FAU - Lin, Dong AU - Lin D AD - Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. dlin6@tulane.edu. FAU - Osman, Hanadi AU - Osman H AD - Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. hosman1@tulane.edu. FAU - Youngquist, Brady AU - Youngquist B AD - Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. byoungquist@tulane.edu. FAU - Scott, John W AU - Scott JW AD - Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. jscottmd@tulane.edu. FAU - Shores, Nathan J AU - Shores NJ AD - Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. shoresnj@gmail.com. FAU - Thevenot, Paul AU - Thevenot P AD - Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA. paul.thevenot@oschner.org. FAU - Cohen, Ari AU - Cohen A AD - Liver Transplant Surgery Section, Ochsner Medical Center, New Orleans, LA 70121, USA. acohen@oschner.org. FAU - Dash, Srikanta AU - Dash S AD - Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. sdash@tulane.edu. AD - Section of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. sdash@tulane.edu. LA - eng GR - AI103106/NH/NIH HHS/United States GR - 1I0OBX004516-01A1/VA Merit Review Grant/ GR - CA089121/NH/NIH HHS/United States GR - U54 GM104940/GM/NIGMS NIH HHS/United States GR - 1P20GM11288-01/NH/NIH HHS/United States PT - Journal Article DEP - 20190920 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC6827087 OTO - NOTNLM OT - cirrhosis OT - endoplasmic reticulum (ER) stress OT - hepatitis C virus (HCV) OT - hepatocellular carcinoma (HCC) OT - hepatocyte nuclear factor 4 alpha (HNF4A) OT - microRNA-122 (miR-122) OT - nuclear factor erythroid 2-related factor 2 (NRF2) OT - oxidative stress (OS) OT - signal transducer and activator of transcription 3 (STAT3) OT - unfolded protein response (UPR) COIS- The authors declare that there is no conflict of interest associated with this manuscript. EDAT- 2019/09/25 06:00 MHDA- 2019/09/25 06:01 PMCR- 2019/09/20 CRDT- 2019/09/25 06:00 PHST- 2019/08/20 00:00 [received] PHST- 2019/09/14 00:00 [revised] PHST- 2019/09/16 00:00 [accepted] PHST- 2019/09/25 06:00 [entrez] PHST- 2019/09/25 06:00 [pubmed] PHST- 2019/09/25 06:01 [medline] PHST- 2019/09/20 00:00 [pmc-release] AID - cancers11101407 [pii] AID - cancers-11-01407 [pii] AID - 10.3390/cancers11101407 [doi] PST - epublish SO - Cancers (Basel). 2019 Sep 20;11(10):1407. doi: 10.3390/cancers11101407.