Abstract
Persistent hepatitis C virus (HCV) infection is associated with high incidence of hepatocellular carcinoma (HCC), the most common primary malignancy of the liver with over half a million new cases diagnosed annually worldwide. The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed transcription factor and its activation by environmental chemicals and by its endogenous ligand kynurenine (Kyn) has been implicated in a variety of tumour-promoting processes such as transformation, tumorigenesis and in immunosuppression that enables tumour survival and growth. Kyn is generated constitutively by human tumour cells via tryptophan (Trp)-2,3-dioxygenase (TDO), a Trp-degrading enzyme expressed in liver, brain and cancer cells. Notably, it has been shown that TDO-derived Kyn suppresses anti-tumour immune responses, thus promoting tumour-cell survival through activation of the AhR pathway. In the context of HCV infection-associated HCC, it was shown that AhR signalling is increased in HCV-infected hepatocytes, and that modifications in the expression of AhR pathway-specific genes are associated with the progression of HCV infection into HCC. Based on these observations, we present and discuss here the hypothesis that HCV infection promotes HCC by modulation of the TDO–Kyn–AhR pathway, resulting in tumorigenesis as well as in suppression of both anti-HCV and anti-tumour immune responses.
Highlights
PRESENTATION OF THE HYPOTHESIS We propose that hepatitis C virus (HCV) infection promotes hepatocellular carcinoma (HCC) by augmentation of the tryptophan (Trp)-2,3-dioxygenase-kynurenine-aryl hydrocarbon receptor (TDO–Kyn–AhR) pathway, resulting in suppression of both anti-HCV and anti-tumour immune responses, as well as in tumorigenesis
Only few genes were found to be differentially expressed in HCV-induced HCC tumour biopsies compared with paired non-HCC liver sections, pathway analysis revealed strong upregulation of genes involved in AhR signalling in biopsies from HCV-induced HCC tumours.[1,2,3]
Based on the above evidence, we propose that manipulation of the TDO–Kyn–AhR pathway by HCV has a pathogenic role in the HCV-infected liver through bystander suppression of anti-tumour immune responses, allowing the progression of HCV infection into HCC
Summary
PRESENTATION OF THE HYPOTHESIS We propose that hepatitis C virus (HCV) infection promotes hepatocellular carcinoma (HCC) by augmentation of the tryptophan (Trp)-2,3-dioxygenase-kynurenine-aryl hydrocarbon receptor (TDO–Kyn–AhR) pathway, resulting in suppression of both anti-HCV and anti-tumour immune responses, as well as in tumorigenesis.
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