Abstract
BackgroundAflatoxin B1 (AFB1) contamination of food is very high in most sub-Saharan African countries. AFB1 is 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 AFB1 deregulation of the type I interferon (IFN) signalling pathway, with consequent HCC is largely unknown. This current study seeks to test the hypothesis that AFB1 inhibits the type I IFN response by directly interfering with key signalling proteins and thus increase the risk of HCC in humans.MethodsWe evaluated the effects of AFB1 on the type I IFN signalling pathway using IFN stimulated response element (ISRE)-based luciferase reporter gene assay. In addition, the effects of AFB1 on the transcript levels of JAK1, STAT1 and OAS3 were assessed by real-time quantitative polymerase chain reaction (RT-qPCR) and confirmed by immunoblot assay.ResultsOur results indicated that AFB1 inhibited the type I IFN signalling pathway in human hepatoma cell line HepG2 cells by suppressing the transcript levels of JAK1, STAT1 and OAS3. AFB1 also decreased the accumulation of STAT1 protein.ConclusionThe inhibition of the type I IFN anti-cancer response pathway by AFB1 suggest a novel mechanism by which AFB1 may induce hepatocellular carcinoma in humans.
Highlights
Aflatoxin B1 (AFB1) contamination of food is very high in most sub-Saharan African countries
AFB1, a lethal mycotoxin produced by Aspergillus flavus and Aspergillus parasiticus is a potent hepatocarcinogen in humans [3, 4] and in view of that it has been classified as group 1 human carcinogen by the International Agency for Research on Cancer (IARC) [5]
The current study has revealed for the first time the inhibition of the type I IFN response pathway by AFB1 via the inhibition of the transcripts of Janus activated kinase 1 (JAK1), Signal transducer and activator of transcription 1 (STAT1) and Oligo adenylate synthetase 3 (OAS3) and inhibit the protein accumulation of STAT1
Summary
Aflatoxin B1 (AFB1) contamination of food is very high in most sub-Saharan African countries. The mechanism behind AFB1 deregulation of the type I interferon (IFN) signalling pathway, with consequent HCC is largely unknown. This current study seeks to test the hypothesis that AFB1 inhibits the type I IFN response by directly interfering with key signalling proteins and increase the risk of HCC in humans. Food meant for human and animal consumption have been reported to contain high levels of aflatoxins in some West African countries such as Ghana, Togo, Nigeria and Benin [6,7,8] largely due to sub-optimal farming practices, high humidity and poor storage conditions. Cereal based foods are staple in Ghana in particular and sub-Saharan Africa in general, it means many more people are exposed to high levels of aflatoxins and increasing their risk of HCC
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