HCV Interplay With Mir34a: Implications in Hepatocellular Carcinoma.

Ester Badami,Cinzia Maria Chinnici,Rosaria Tinnirello,Gioacchin Iannolo,Pier Giulio Conaldi,Claudia Carcione

doi:10.3389/fonc.2021.803278

Abstract

Since its identification, HCV has been considered one of the main causes of hepatitis and liver cancer. Currently, the molecular mechanisms of HCC development induced by HCV infection have not been sufficiently clarified. The recent discovery of novel treatments that inhibit HCV replication gave rise to new questions concerning HCC mechanisms. In particular, the HCV eradication mediated by new direct-acting antiviral (DAAs) drugs does not exclude the possibility of de novo HCC development; this finding opened more questions on the interplay between liver cells and the virus. Different groups have investigated the pathways leading to cancer recurrence in patients treated with DAAs. For this reason, we tried to gain molecular insights into the changes induced by HCV infection in the target liver cells. In particular, we observed an increase in microRNA34a (miR34a) expression following HCV infection of HCC cell line Huh7.5. In addition, Huh7.5 treated with extracellular vesicles (EVs) from the previously HCV-infected Huh7.5 underwent apoptosis. Since miR34 expression was increased in Huh7.5 EVs, we hypothesized a paracrine mechanism of viral infection mediated by miR34a cargo of EVs. The balance between viral infection and cell transformation may raise some questions on the possible use of antiviral drugs in association with antineoplastic treatment.

Highlights

Liver cancer is the fourth cause of cancer death worldwide [1], among which hepatocellular carcinoma (HCC) accounts for 75%–85%
In order to evaluate whether hepatitis C virus (HCV) infection can cause an increase of miR34 expression in target cells, as observed for Zika virus (ZIKV), and induce a cytostatic/cytotoxic effect, we addressed molecular changes in Huh7.5 before and after HCV infection
Other authors have described an increase in miR34 expression after HCV infection, in serum of patients with chronic hepatitis C [38]

Summary

Introduction

Liver cancer is the fourth cause of cancer death worldwide [1], among which hepatocellular carcinoma (HCC) accounts for 75%–85%. Chronic infection caused by hepatitis C virus (HCV) is one of the most common HCC risk factors [1]. Apart from this, there is no well-defined connection for HCV infection and HCC induction, various mechanisms have been evaluated [4,5,6]. Direct-acting antivirals (DAAs) represent a longexpected solution for HCV treatment [7, 8], and several studies demonstrated the benefit of DAA regimen before HCC diagnosis, with an increased median survival up to 5 years [9]. Interferon (IFN)-free DAA treatment is well tolerated and was associated with improved survival [10]; recent reports showed that DAA treatment does not completely avoid the occurrence of HCC [11,12,13], raising a great debate on the consequence of this treatment and the need for screening after viral eradication [14, 15]

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Results

Conclusion