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Background
Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, leads
to a median survival of less than one year, necessitating the search for new therapies.
The cytosolic helicase RIG-I senses viral 5′-triphosphate-RNA (ppp-RNA) and induces
type I interferon (IFN)-driven immune responses that combat both viral infections
as well as tumours. RIG-I may thus serve as a new target for immunotherapy of HCC.
Methods
RIG-I expression in HCC was analysed by immunohistochemistry (IHC) and WB. RIG-I functional
activity was assessed by transfection of HCC cells with ppp-RNA. Therapeutic efficacy
was evaluated in vitro and in vivo in an orthotopic HCC mouse model. Seven days after tumour induction ppp-RNA was injected
intravenous (i.v.) and survival was monitored. Tumour tissue was analysed via IHC
and qRT-PCR.
Results
Treatment of human and murine HCC cells with ppp-RNA induced phosphorylation of IRF-3,
production of IFN-b and CXCL10, indicative of intact RIG-I signalling. In addition,
RIG-I activation led to profound tumour cell death. Treatment of mice with orthotopic
HCC with ppp-RNA reduced tumour size and significantly prolonged survival. CD8+ T
cells as well as NK cells mediated tumour rejection.
Conclusion
Our data demonstrate that RIG-I is functional in HCC. RIG-I activation leads to systemic
and intratumoural type I IFN production accompanied by massive tumour cell death in vitro and in vivo. RIG-I is thus a promising novel target for HCC therapy deserving further evaluation.
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