Giovannini Catia, Fornari Francesca, Indio Valentina, Trerè Davide, Renzulli Matteo, Vasuri Francesco, Cescon Matteo, Ravaioli Matteo, Perrucci Alessia, Astolfi Annalisa, Piscaglia Fabio, Gramantieri Laura
Center for Applied Biomedical Research (CRBA), Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy.
Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy.
Cancers (Basel). 2020 Sep 19;12(9):2674. doi: 10.3390/cancers12092674.
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.
直接作用抗病毒药物（DAA）根除丙型肝炎病毒可降低肝硬化患者新发肝细胞癌（HCC）的发生率；然而，对于已经发生HCC的患者，关于其有益或有害影响的证据仍存在矛盾。
我们研究了索磷布韦和达卡他韦是否会调节HCC来源细胞系中的细胞增殖、侵袭能力和基因表达（RNA测序），推测这些药物可能存在脱靶效应。在HCC细胞系中观察到的结果通过qPCR和免疫组化在非HCC癌症来源细胞系和一系列人类HCC组织中得到验证。
DAA可通过增加或降低HCC细胞增殖和迁移能力来影响它们，显示出与一些意外的药物相关效应一致的转录组变化。脱靶基因调节主要影响核糖体基因、线粒体功能和组蛋白，表明表观遗传学和增殖是相关事件，与匹配的表型变化一致。在先前接受过DAA治疗的HCC患者的有限队列中对体外研究结果进行了初步验证，免疫组化相关性表明接受DAA治疗的HCC在迁移和上皮-间质转化方面更具侵袭性。
我们的研究结果表明可能发生脱靶效应，最终调节细胞增殖和/或迁移，并可能解释了先前的研究结果，即显示出一些特别侵袭性的HCC复发实例以及DAA治疗后HCC复发率降低的情况。
