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

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.

Low Molecular Weight Fucoidan Prevents Radiation-Induced Fibrosis and Secondary Tumors in a Zebrafish Model

“…Therefore, hnf4a was determined to be a driver gene. It was reported that stress-induced inhibition of HNF4A expression is related to liver fibrosis and cancer formation [ 58 ]. Overexpressed Hnf5a resets the transcription factor network in hepatocytes and prevents hepatic failure [ 59 ].…”

Circulating miRNAs Associated With ER Stress and Organ Damage in a Preclinical Model of Trauma Hemorrhagic Shock

“…MiR-122 was also found to play a role in the hypoxia responses that regulate glucose and energy metabolism (51). In addition, it was recently reported that ER stress impacts on miR-122 promoter activity (52). We found miR-638, miR−135a-5p, miR−135b-5p, miR-668-3p, miR-204-5p, miR−146a-5p, miR−200a-3p, miR−17-5p, miR−30a-5p, and miR−214-3p strongly correlated with lactate, base excess, and bicarbonate.…”

Targeting STAT3 and STAT5 in Cancer

“…STAT3 activation was also explored in hepatocellular carcinoma (HCC) arising from hepatitis C infections. Aydin et al identified that HCC progression was mediated through NRF2, leading to STAT3 activation and suppression of miR-122 [ 36 ]. Finally, nano-formulated STAT3 inhibitors were also shown to be effective in myeloma xenograft models, enhancing the therapeutic properties of the inhibitor alone [ 37 ].…”