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AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma.

ABSTRACT: Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma (HCC) in individuals infected with the hepatitis virus. However, the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined. Here, we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1 (AFB1) targets. Among the most significant hits was the aryl hydrocarbon receptor (AHR), a ligand-binding transcription factor regulating cell metabolism, differentiation, and immunity. AHR-deficient cells tolerated high concentrations of AFB1, in which AFB1 adduct formation was significantly decreased. AFB1 triggered AHR nuclear translocation by directly binding to its N-terminus. Furthermore, AHR mediated the expression of P450 induced by AFB1. AHR expression was also elevated in primary tumor sections obtained from AFB1-HCC patients, which paralleled the upregulation of PD-L1, a clinically relevant immune regulator. Finally, anti-PD-L1 therapy exhibited greater efficacy in HCC xenografts derived from cells with ectopic expression of AHR. These results demonstrated that AHR was required for the AFB1 toxicity associated with HCC, and implicate the immunosuppressive regimen of anti-PD-L1 as a therapeutic option for the treatment of AFB1-associated HCCs.

SUBMITTER: Zhu Q

PROVIDER: S-EPMC8352983 | biostudies-literature |

REPOSITORIES: biostudies-literature

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In vitro recapitulating of TP53 mutagenesis in hepatocellular carcinoma associated with dietary aflatoxin B1 exposure.

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Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-05-10 | GSE71549 | GEO

Aflatoxin B1 DNA-Adducts in Hepatocellular Carcinoma from a Low Exposure Area.

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Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma [mRNA]

Project description:Chronic exposure to aflatoxin B1 (AFB1) has, in certain regions in the world, been strongly associated with the development of hepatocellular carcinoma (HCC). AFB1 is a very potent hepatotoxic and carcinogenic mycotoxin which is frequently reported as a food contaminant. Epigenetic modifications provoked by environmental exposures, such as AFB1, may create a so called persistent "epigenetic memory" or "footprint". Deregulation of epigenetic mechanisms has actually been reported in HCC patients following AFB1 exposure; however no attempts have yet been made to investigate early effects on the epigenome level which may be persistent on longer term thereby possibly initiating carcinogenic events. In this study, we aim to identify methyl DNA-mRNA-interactions representative for a persistent epigenetic "footprint" associated with the early onset of AFB1-induced HCC. For this, primary human hepatocytes were exposed to 0.3 µM of AFB1 for 5 days. Persistent epigenetic effects were m easured 3 days after terminating the carcinogenic treatment. Whole genome DNA methylation changes and whole genome transcriptomic analysis were analyzed applying microarray technologies, and cross-omics interactions were evaluated. Upon combining transcriptomics data with results on DNA methylation, a range of persistent hyper- and hypomethylated genes was identified which appeared also affected on the transcriptome level. For six of the hypomethylated and upregulated genes, namely TXNRD1, PCNA, CCNK, DIAPH3, RAB27A and HIST1H2BF, a clear role in carcinogenic events could be identified. This study is the first to report on a carcinogen-induced persistent impact on the "epigenetic footprint" in relation with the transcriptome which could be indicative for the early onset of AFB1-related development of HCC.

2016-05-10 | GSE71547 | GEO

Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma [miRNA]

2016-05-10 | GSE71545 | GEO

Aflatoxin B1 exposure increases the risk of hepatocellular carcinoma associated with hepatitis C virus infection or alcohol consumption.

Project description:BACKGROUND:Hepatocarcinogenicity of aflatoxin B1 (AFB1) has rarely been studied in populations with hepatitis C virus (HCV) infection and those without hepatitis B virus (HBV) and HCV infection (non-B-non-C). This case-control study nested in a community-based cohort aimed to investigate the HCC risk associated with AFB1 in HCV-infected and non-B-non-C participants. METHODS:Baseline serum AFB1-albumin adduct levels were measured in 100 HCC cases and 1767 controls seronegative for anti-HCV and HBsAg (non-B-non-C), and another 103 HCC cases and 176 controls who were anti-HCV-seropositive and HBsAg-seronegative. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. RESULTS:In 20 years of follow-up, the follow-up time to newly developed HCC was significantly shorter in participants with higher serum AFB1-albumin adduct levels in non-B-non-C (p = 0.0162) and HCV-infected participants (p < 0.0001). Within 8 years of follow-up, HCV infection and AFB1 exposure were independent risk factors for HCC. Elevated serum AFB1-albumin adduct levels were significantly associated with an increased risk of HCC newly developed within 8 years of follow-up in non-B-non-C participants with habitual alcohol consumption [crude OR (95% CI) for high vs. low/undetectable levels, 4.22 (1.16-15.37)] and HCV-infected participants [3.39 (1.31-8.77)], but not in non-B-non-C participants without alcohol drinking habit. AFB1 exposure remained an independent risk predictor for HCV-related HCC after adjustment for other HCC predictors (multivariate-adjusted OR [95% CI], 3.65 [1.32-10.10]). CONCLUSIONS:AFB1 exposure contributes to the development of HCC in participants with significant risk factors for cirrhosis including alcohol and HCV infection.

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Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma [DNA methylation]

2016-05-10 | GSE71548 | GEO

Interaction of DNA repair gene polymorphisms and aflatoxin B1 in the risk of hepatocellular carcinoma.

Project description:Aflatoxin B1 (AFB1) is an important environmental carcinogen and can induce DNA damage and involve in the carcinogenesis of hepatocellular carcinoma (HCC). The deficiency of DNA repair capacity related to the polymorphisms of DNA repair genes might play a central role in the process of HCC tumorigenesis. However, the interaction of DNA repair gene polymorphisms and AFB1 in the risk of hepatocellular carcinoma has not been elucidated. In this study, we investigated whether six polymorphisms (including rs25487, rs861539, rs7003908, rs28383151, rs13181, and rs2228001) in DNA repair genes (XPC, XRCC4, XRCC1, XRCC4, XPD, XRCC7, and XRCC3) interacted with AFB1, and the gene-environmental interactive role in the risk of HCC using hospital-based case-control study (including 1486 HCC cases and 1996 controls). Genotypes of DNA repair genes were tested using TaqMan-PCR technique. Higher AFB1 exposure was observed among HCC patients versus the control group [odds ratio (OR) = 2.08 for medium AFB1 exposure level and OR = 6.52 for high AFB1 exposure level]. Increasing risk of HCC was also observed in these with the mutants of DNA repair genes (risk values were from 1.57 to 5.86). Furthermore, these risk roles would be more noticeable under the conditions of two variables, and positive interactive effects were proved in the followed multiplicative interaction analysis. These results suggested that DNA repair risk genotypes might interact with AFB1 in the risk of HCC.

| S-EPMC4203246 | biostudies-literature

Aflatoxin B1 exposure induces epigenetic mechanisms in primary human hepatocytes revealing novel biological processes associated with hepatocellular carcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-05-10 | GSE67078 | GEO

Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers.

Project description:The relation between aflatoxin B1 (AFB1 ) and cirrhosis in chronic carriers of hepatitis B virus (HBV) remains inconclusive. This case-control study nested in a large community-based cohort aimed to assess the effect of AFB1 exposure on cirrhosis and HCC in chronic HBV carriers. Serum AFB1 -albumin adduct levels at study entry were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls. Multivariate-adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. Among all chronic HBV carriers, the time intervals between study entry and diagnosis of HCC, cirrhosis, cirrhotic HCC, and non-cirrhotic HCC were all significantly (p?<?0.0001) shorter in participants with high serum levels of AFB1 -albumin adducts than those with low/undetectable levels. There were significant dose-response relations with serum AFB1 -albumin adduct level at study entry for cirrhosis (p-trend?=?0.0001) and cirrhotic HCC (p-trend?<?0.0001) newly diagnosed within 9 years after entry as well as non-cirrhotic HCC (p-trend?=?0.021) newly diagnosed within 4 years after entry. The aORs (95% CIs) for high versus undetectable serum AFB1 -albumin adduct levels were 2.45 (1.51-3.98) for cirrhosis (p?=?0.0003), 5.47 (2.20-13.63) for cirrhotic HCC (p?=?0.0003), and 5.39 (1.11-26.18) for non-cirrhotic (p?=?0.0368) HCC, respectively. There remained a significant dose-response relation between serum AFB1 -albumin adduct level and HCC risk (p-trend?=?0.0291) in cirrhosis patients, showing an aOR (95% CI) of 3.04 (1.11-8.30) for high versus undetectable serum levels (p?=?0.0299). It is concluded that AFB1 exposure may increase the risk of cirrhosis and HCC in a dose-response manner among chronic HBV carriers.

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