Abstract
HCV eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma (HCC) incidence in cirrhosis; however, contrasting evidence about beneficial or detrimental effects still exists in patients who have already developed HCC. we investigated whether sofosbuvir and daclatasvir modulate cell proliferation, invasion capability and gene expression (RNA-seq) in HCC-derived cell lines, hypothesizing possible off-target effects of these drugs. Results observed in HCC cell lines were validated in non-HCC cancer-derived cell lines and a preliminary series of human HCC tissues by qPCR and IHC. DAAs can affect HCC cell proliferation and migration capability by either increasing or reducing them, showing transcriptomic changes consistent with some unexpected drug-associated effects. Off-target gene modulation, mainly affecting ribosomal genes, mitochondrial functions and histones, points to epigenetics and proliferation as relevant events, consistent with matched phenotypic changes. A preliminary validation of in vitro findings was performed in a restricted cohort of HCC patients previously treated with DAAs, with immunohistochemical correlations suggesting DAA-treated HCCs to be more aggressive in terms of migration and epidermal-to-mesenchymal transition. Our findings suggested the possible occurrence of off-target effects ultimately modulating cell proliferation and/or migration and potentially justified previous findings showing some instances of particularly aggressive HCC recurrence as well as reduced incidence of recurrence of HCC following treatment with DAAs.
Highlights
In western countries as well as in Japan, a large proportion of hepatocellular carcinomas (HCCs) are associated with hepatitis C virus (HCV) infection in the cirrhotic stage
Our first question was whether a single administration of sofosbuvir and/or daclatasvir plays any effect on HCC cell proliferation
We performed a preliminary screening of five HCC-derived cell lines (SNU449, SNU475, Huh7, HepG2 and Hep3B) by crystal violet staining after exposure to either sofosbuvir and/or daclatasvir
Summary
In western countries as well as in Japan, a large proportion of hepatocellular carcinomas (HCCs) are associated with hepatitis C virus (HCV) infection in the cirrhotic stage. The target mechanism of action is inhibition of viral replication by blocking non-structural viral proteins. A significant reduction in first HCC incidence results from HCV eradication by DAAs [1]. HCV eradication by direct-acting antiviral agents (DAAs) reduces de novo hepatocellular carcinoma (HCC) incidence in cirrhosis; contrasting evidence about beneficial or detrimental effects still exists in patients who have already developed HCC. Methods: we investigated whether sofosbuvir and daclatasvir modulate cell proliferation, invasion capability and gene expression (RNA-seq) in HCC-derived cell lines, hypothesizing possible off-target effects of these drugs. Results: DAAs can affect HCC cell proliferation and migration capability by either increasing or reducing them, showing transcriptomic changes consistent with some unexpected drug-associated effects.
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