中文摘要：在大多数撒哈拉以南的非洲国家，黄曲霉毒素B1（AFB1）对食品污染非常严重。众所周知，AFB1通过诱导肿瘤抑制基因TP53突变而引起肝细胞癌（HCC）。西非新增HCC病例数量居高不下，并伴随着高死亡率。先天免疫系统的I型干扰素（IFN）通路抑制了病毒感染，并通过上调肿瘤抑制基因活性和促凋亡通路来发挥其抗癌特性。事实上，据报道IFN-α对抗肝纤维化及肝癌有显著的保护作用。然而，AFB1阻碍I型干扰素（IFN）信号通路的调控，随后引发HCC的机制在很大程度上是未知的。本研究旨在测试AFB1通过直接干扰关键信号蛋白来抑制I型IFN反应，从而增加人类患HCC的风险的假设。
结果发现AFB1对I型IFN抗癌反应通路的抑制提出了一种新的机制，即AFB1可诱导人类肝细胞癌。
外文摘要：Background Aflatoxin 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. Methods We 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. Results Our 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. Conclusion The 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.
外文关键词：Aflatoxin B-1；Hepatocellular carcinoma；STAT1；Type I interferon pathway；HepG2 cells；JAK1；ISRE
作者：Narkwa, PW；Blackbourn, DJ；Mutocheluh, M
作者单位：Kwame Nkrumah Univ Sci & Technol
期刊名称：INFECTIOUS AGENTS AND CANCER
期刊影响因子：1.718
出版年份：2017
出版刊次：3
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