Project description:Hepatocellular carcinoma (HCC), one of the most common cancer types, is a multi-factorial disease. One strongly associated factor is oral exposure to the food-contaminant aflatoxin B1 (AFB1). A clear link between AFB1-induced p53 mutations and HCC exists, however less is known about the association with microRNA expression changes. In particular, irreversible adverse effects that may occur at the transcriptomic level following repetitive exposure have not been investigated yet. Therefore, in this study, we aimed to dissect persistent changes in expression of microRNA-directed regulatory networks from transient transcriptome modifications contributing to AFB1-induced HCC. Primary human hepatocytes were exposed to 1 µM of AFB1 for 5 days followed by a 3 day wash-out period. Whole genome transcriptomic analysis and microRNA expressions were analyzed applying microarray technologies. By evaluating genes which remain significantly expressed into the same direction after the 3-day wash-out period persistent AFB1-induced and HCC-related biological processes could be identified. Persistent genes could be linked with "Drug and energy metabolism" and "Pre-, post- and transcriptional regulation of gene expression" related processes. Especially, two HCC-related microRNAs, hsa-miR-34b-5p and hsa-miR-222-3p, which are persistently expressed, seem to regulate genes involved in these very characteristic AFB1-induced processes referring to cancer-associated metabolism changes and regulation of gene expression. Moreover, hsa-miR-34a-5p, hsa-miR-96-5p and hsa-miR-30a-3p which become differentially expressed only upon terminating AFB1 exposure, seem to regulate persistently expressed genes. The findings within this study therefore contribute to a better understanding of the AFB1-induced onset of HCC by causing persistent effects on microRNA and gene expression.
Project description:Hepatocellular carcinoma (HCC), one of the most common cancer types, is a multi-factorial disease. One strongly associated factor is oral exposure to the food-contaminant aflatoxin B1 (AFB1). A clear link between AFB1-induced p53 mutations and HCC exists, however less is known about the association with microRNA expression changes. In particular, irreversible adverse effects that may occur at the transcriptomic level following repetitive exposure have not been investigated yet. Therefore, in this study, we aimed to dissect persistent changes in expression of microRNA-directed regulatory networks from transient transcriptome modifications contributing to AFB1-induced HCC. Primary human hepatocytes were exposed to 1 µM of AFB1 for 5 days followed by a 3 day wash-out period. Whole genome transcriptomic analysis and microRNA expressions were analyzed applying microarray technologies. By evaluating genes which remain significantly expressed into the same direction after the 3-day wash-out period persistent AFB1-induced and HCC-related biological processes could be identified. Persistent genes could be linked with "Drug and energy metabolism" and "Pre-, post- and transcriptional regulation of gene expression" related processes. Especially, two HCC-related microRNAs, hsa-miR-34b-5p and hsa-miR-222-3p, which are persistently expressed, seem to regulate genes involved in these very characteristic AFB1-induced processes referring to cancer-associated metabolism changes and regulation of gene expression. Moreover, hsa-miR-34a-5p, hsa-miR-96-5p and hsa-miR-30a-3p which become differentially expressed only upon terminating AFB1 exposure, seem to regulate persistently expressed genes. The findings within this study therefore contribute to a better understanding of the AFB1-induced onset of HCC by causing persistent effects on microRNA and gene expression.
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.
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.
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.
Project description:Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and its occurrence is associated with a number of environmental factors including ingestion of the dietary contaminant aflatoxin B1 (AFB1). While etiology of the disease is relatively well defined, the molecular mechanisms of tumorigenesis are poorly understood. In this study, we examined, for the first time, gene expression of AFB1-induced HCC by microarray in the rainbow trout (Oncorhynchus mykiss) tumor model. Carcinogenesis was initiated in trout embryos with 50 ppb AFB1 and 13 months later control livers, tumors and tumor-adjacent liver tissues were isolated from juvenile fish. Global gene expression was determined in histologically confirmed HCCs compared to non-cancerous adjacent tissue and sham-initiated control liver utilizing a rainbow trout oligonucleotide array containing approximately 1500 genes of known or probable relevance to toxicology, comparative immunology, carcinogenesis and stress physiology. We observed distinct gene regulation patterns in HCC compared to non-cancerous tissue including upregulation of genes important for cell cycle control, transcription, cytoskeletal formation and the acute phase response and down regulation of genes involved in drug metabolism, lipid metabolism and retinol metabolism. These gene classes have previously been observed to be important in the regulation of HCC in human and rodent models. Overall, these findings contribute to a better understanding of the mechanism of AFB1-induced hepatocarcinogenesis in the trout model and identify conserved genes important for carcinogenesis in species separated evolutionarily by more than 400 million years. Keywords: other
Project description:Comparison of gene expression profiles induced by the mycotoxin, aflatoxin B1 (AFB1), in primary human hepatocytes and HepaRG cells. Initial mechanisms involved in the complex multistep process leading to malignant transformation by chemicals remain largely unknown. We have analysed changes in gene expression profiles in primary human hepatocytes and differentiated human hepatoma HepaRG cells after a 24 h treatment with 0.05 or 0.25µM aflatoxin B1 (AFB1), a potent genotoxic hepatocarcinogen.
Project description:Comparison of gene expression profiles induced by the mycotoxin, aflatoxin B1 (AFB1), in primary human hepatocytes and HepaRG cells. Initial mechanisms involved in the complex multistep process leading to malignant transformation by chemicals remain largely unknown. We have analysed changes in gene expression profiles in primary human hepatocytes and differentiated human hepatoma HepaRG cells after a 24 h treatment with 0.05 or 0.25µM aflatoxin B1 (AFB1), a potent genotoxic hepatocarcinogen. Three independent biological replicates of HepaRG cell cultures and two pools of three primary human hepatocyte cultures each, were investigated. Cells were treated with 0.05 or 0.25µM AFB1 for 24 h.
Project description:Aflatoxin B1 (AFB1) is a mycotoxin produced by Aspergillus flavus and A. parasiticus. AFB1 targeted gene expression profiles were determined in human primary trophoblast cells, isolated from full term placentae after delivery, and exposed to 1 µM AFB1 for 72 hours. Gene expression profiling conducted with human HT-12 expression beadchips
Project description:Aflatoxin B1 (AFB1) is a mutagen and IARC (International Agency for Research on Cancer) Group 1 carcinogen that causes hepatocellular carcinoma (HCC). Here we present the first whole genome data on the mutational signatures of AFB1 exposure from a total of > 40,000 mutations in four experimental systems: two different human cell lines, and in liver tumors in wild-type mice and in mice that carried a hepatitis B surface antigen transgene – this to model the multiplicative effects of aflatoxin exposure and hepatitis B in causing HCC. AFB1 mutational signatures from all four experimental systems were remarkably similar. We integrated the experimental mutational signatures with data from newly-sequenced HCCs from Qidong County, China, a region of well-studied aflatoxin exposure. This indicated that COSMIC mutational signature 24, previously hypothesized to stem from aflatoxin exposure, indeed likely represents AFB1 exposure, possibly combined with other exposures. Among published somatic mutation data, we found evidence of AFB1 exposure in 0.7% of HCCs treated in North America, 1% of HCCs from Japan, but 16% of HCCs from Hong Kong. Thus, aflatoxin exposure apparently remains a substantial public health issue in some areas. This aspect of our study exemplifies the promise of future widespread resequencing of tumor genomes in providing new insights into the contribution of mutagenic exposures to cancer incidence.