Aflatoxin B1inhibits the type 1 interferon response pathway via STAT1 suggesting another mechanism of hepatocellular carcinoma.
BACKGROUND
Aflatoxin B1(AFB1) contamination of food is very high in most sub-Saharan African countries. AFB1is known to cause hepatocellular carcinoma (HCC) by inducing mutation in the tumour suppressor gene TP53. The number of new HCC cases is high in West Africa with an accompanying high mortality. The type I interferon (IFN) pathway of the innate immune system limits viral infections and exerts its anti-cancer property by up-regulating tumour suppressor activities and pro-apoptotic pathways. Indeed, IFN-α is reported to show significant protective effects against hepatic fibrogenesis and carcinogenesis. However, the mechanism behind AFB1deregulation of the type I interferon (IFN) signalling pathway, with consequent HCC is largely unknown. This current study seeks to test the hypothesis that AFB1inhibits the type I IFN response by directly interfering with key signalling proteins and thus increase the risk of HCC in humans.


METHODS
We evaluated the effects of AFB1on the type I IFN signalling pathway using IFN stimulated response element (ISRE)-based luciferase reporter gene assay. In addition, the effects of AFB1on the transcript levels ofJAK1,STAT1andOAS3were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) and confirmed by immunoblot assay.


RESULTS
Our results indicated that AFB1inhibited the type I IFN signalling pathway in human hepatoma cell line HepG2 cells by suppressing the transcript levels ofJAK1,STAT1andOAS3. AFB1also decreased the accumulation of STAT1 protein.


CONCLUSIONS
The inhibition of the type I IFN anti-cancer response pathway by AFB1suggest a novel mechanism by which AFB1may induce hepatocellular carcinoma in humans.
Department of Clinical Microbiology, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Patrick W
PW
Narkwa
Department of Microbial and Cellular Sciences, School of Biosciences and Medicine, University of Surrey, Surrey, GU2 7XH UK.
David J
DJ
Blackbourn
Department of Clinical Microbiology, School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Mohamed
M
Mutocheluh
Aflatoxin B1; HepG2 cells; Hepatocellular carcinoma; ISRE; JAK1; STAT1; Type I interferon pathway