Intrahepatic Cholangiocarcinoma (iCCA), bile duct cancer, is increasing in incidence worldwide. Infection with hepatitis C virus (HCV) is a known risk factor for developing iCCA. Recent studies of HCV associated hepatocellular carcinoma (HCC) have demonstrated that HCV infection induces oncogenic gene expression patterns resulting from altered epigenetic profiles. Importantly, whilst ∼90% of patients treated with new direct acting antivirals (DAAs) attain a sustained virological response, the risk of HCC and other malignancies is not reduced by the same extent as previous interferon therapies. We, and others, have shown that this may be related to an imprinted gene expression pattern persisting post-treatment.

The cellular origin of primary liver cancers can vary due to liver cell plasticity. However, the incidence of mixed iCCA-HCC tumour phenotypes and the dual iCCA/HCC risk associated with HCV infection led us to hypothesise that virus-infected hepatic progenitor cells (HPC) might be the source of virus-driven malignancies. Accordingly, we demonstrated that adult HPCs were susceptible to HCV infection . Moreover, models of hepatic differentiation revealed that HCV disrupts this process via hijacking the HIPPO signalling pathway with oncogenic hallmarks persisting following viral cure.

To explore HCV-induced alterations during cholangiocyte-specific differentiation, we have chosen to exploit the immortalised non-transformed HPC line, HepaRG and induced pluripotent stem cell derived HPCs. We will describe endeavours to develop a robust model of HCV-mediated perturbation of cholangiocyte-specific differentiation in order to identify new treatments that complement DAA therapy in order to eliminate the risk of malignancy.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.

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