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Unique microRNA Alterations in Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice

ABSTRACT: Unique microRNA Alterations in Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice

PROVIDER: PRJNA578909 | ENA |

REPOSITORIES: ENA

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Unique microRNA Alterations in Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice

Project description:Ginkgo biloba leaf extract (GBE) is used in traditional Chinese medicine as an herbal supplement for improving memory. Exposure of B6C3F1/N mice to GBE in a 2-year National Toxicology Program (NTP) bioassay resulted in a dose-dependent increase in hepatocellular carcinomas (HCC). To identify key microRNAs that modulate GBE-induced hepatocarcinogenesis, we compared the global miRNA expression profiles in GBE-exposed HCC (GBE-HCC) and spontaneous HCC (SPNT-HCC) with age-matched vehicle control normal livers (CNTL) from B6C3F1/N mice. The number of differentially altered miRNAs in GBE-HCC and SPNT-HCC were 74 (52 up and 22 down) and 33 (15 up and 18 down), respectively. Among the uniquely differentially altered miRNAs in GBE-HCC,, miR-31 was selected for functional validation. A potential miRNA response element (MRE) in the 3’-untranslated regions (3’-UTR) of Cdk1 mRNA was revealed by in silico analysis and confirmed by luciferase assays. In mouse hepatoma cell line HEPA-1 cells, we demonstrated an inverse correlation between miR-31 and CDK1 protein levels, but no change in Cdk1 mRNA levels, suggesting a post-transcriptional effect. Additionally, miRNA expression analysis in non-tumor liver samples from the 90-day GBE mouse study demonstrated an upregulation of miRs-411, 300, 127, 134, 409-3p, and 433-3p in GBE-exposed group compared to vehicle control group, indicating that some of these miRNAs could serve as potential biomarkers for GBE exposure or hepatocellular carcinogenesis. These data increase our understanding of miRNA-mediated epigenetic regulation of GBE-mediated hepatocellular carcinogenesis in B6C3F1/N mice.

2020-06-02 | GSE139252 | GEO

Expression Profiling of Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice [Expression]

Project description:In a recent NTP study, chronic exposure of B6C3F1/N mice to Ginkgo biloba extract (GBE) resulted in a high incidence of hepatocellular carcinomas (HCC). Genome-wide promoter methylation profiling and Expression profiling on GBE-exposed HCC (2000 mg/kg group), spontaneous HCC (vehicle-control group) and age-matched vehicle control liver was performed to identify differentially methylated genes and differentially expressed genes in GBE-exposed HCC and spontaneous HCC. DNA methylation alterations were correlated to the corresponding global gene expression changes to identify differentially methylated promoter regions of relevant cancer genes altered in GBE-exposed HCC compared to spontaneous HCC.

2020-01-01 | GSE132575 | GEO

Genome-wide promoter DNA Methylation Profiling of Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice [Methylation]

2020-01-01 | GSE132577 | GEO

Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice

Project description:Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice

| PRJNA548385 | ENA

Expression Profiling of Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice [Expression]

Project description:Expression Profiling of Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice [Expression]

| PRJNA548388 | ENA

Unique microRNA alterations in hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice.

Project description:Ginkgo biloba extract (GBE) is used in traditional Chinese medicine as a herbal supplement for improving memory. Exposure of B6C3F1/N mice to GBE in a 2-year National Toxicology Program (NTP) bioassay resulted in a dose-dependent increase in hepatocellular carcinomas (HCC). To identify key microRNAs that modulate GBE-induced hepatocarcinogenesis, we compared the global miRNA expression profiles in GBE-exposed HCC (GBE-HCC) and spontaneous HCC (SPNT-HCC) with age-matched vehicle control normal livers (CNTL) from B6C3F1/N mice. The number of differentially altered miRNAs in GBE-HCC and SPNT-HCC was 74 (52 up and 22 down) and 33 (15 up and 18 down), respectively. Among the uniquely differentially altered miRNAs in GBE-HCC, miR-31 and one of its predicted targets, Cdk1 were selected for functional validation. A potential miRNA response element (MRE) in the 3'-untranslated regions (3'-UTR) of Cdk1 mRNA was revealed by in silico analysis and confirmed by luciferase assays. In mouse hepatoma cell line HEPA-1 cells, we demonstrated an inverse correlation between miR-31 and CDK1 protein levels, but no change in Cdk1 mRNA levels, suggesting a post-transcriptional effect. Additionally, a set of miRNAs (miRs-411, 300, 127, 134, 409-3p, and 433-3p) that were altered in the GBE-HCCs were also altered in non-tumor liver samples from the 90-day GBE-exposed group compared to the vehicle control group, suggesting that some of these miRNAs could serve as potential biomarkers for GBE exposure or hepatocellular carcinogenesis. These data increase our understanding of miRNA-mediated epigenetic regulation of GBE-mediated hepatocellular carcinogenesis in B6C3F1/N mice.

| S-EPMC8077180 | biostudies-literature

Genome-wide promoter DNA Methylation Profiling of Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice [Methylation]

Project description:Genome-wide promoter DNA Methylation Profiling of Hepatocellular Carcinomas Arising Either Spontaneously or due to Chronic Exposure to Ginkgo biloba Extract (GBE) in B6C3F1/N Mice [Methylation]

| PRJNA548387 | ENA

Global gene expression profiling of hepatocellular carcinomas in B6C3F1 mice induced by Ginkgo biloba extract by gavage for two years

Project description:Ginkgo biloba leaf extract (GBE) has been used for centuries in traditional Chinese medicine and today is used as an herbal supplement for various indications such as improving neural function, anti-oxidant and anti-cancer effects. As part of the herbal supplement industry, these compounds are largely unregulated, and may be consumed in large concentrations over extended periods of time. This is of particular concern, because the long-term effects in terms of toxicity and carcinogenicity data is lacking for many herbal products, including GBE. The 2-year B6C3F1 mouse carcinogenicity bioassay indicated a marked dose-related increase in hepatocellular carcinoma (HCC) development associated with exposure to GBE. We have shown that the mechanism of this increase in tumorigenesis is related to a marked increase in the incidence of Î²-catenin mutation, and report a novel mechanism of constitutive Î²-catenin activation through post-translational modification leading to constitutive Wnt signaling and unregulated growth signaling and oncogenesis. Furthermore, using global gene expression profiling, we show that GBE-induced HCC exhibit overrepresentation of gene categories associated with human cancer and HCC signaling including upregulation of relevant oncogenes and suppression of critical tumor suppressor genes, as well as chronic oxidative stress, a known inducer of calpain-mediated degradation and promoter of hepatocarcinogenesis in humans. These data provide a molecular mechanism to GBE-induced HCC in B6C3F1 mice that is relevant to human cancer, and provides relevant molecular data that will provide the groundwork for further risk assessment of unregulated compounds, including herbal supplements. Six hepatocellular carcinomas induced by GBE, six spontaneous hepatocellular carcinomas, and six normal liver samples, three technical replicates each.

2012-12-07 | E-GEOD-29813 | biostudies-arrayexpress

Global gene expression profiling of hepatocellular carcinomas in B6C3F1 mice induced by Ginkgo biloba extract by gavage for two years

Project description:Ginkgo biloba leaf extract (GBE) has been used for centuries in traditional Chinese medicine and today is used as an herbal supplement for various indications such as improving neural function, anti-oxidant and anti-cancer effects. As part of the herbal supplement industry, these compounds are largely unregulated, and may be consumed in large concentrations over extended periods of time. This is of particular concern, because the long-term effects in terms of toxicity and carcinogenicity data is lacking for many herbal products, including GBE. The 2-year B6C3F1 mouse carcinogenicity bioassay indicated a marked dose-related increase in hepatocellular carcinoma (HCC) development associated with exposure to GBE. We have shown that the mechanism of this increase in tumorigenesis is related to a marked increase in the incidence of β-catenin mutation, and report a novel mechanism of constitutive β-catenin activation through post-translational modification leading to constitutive Wnt signaling and unregulated growth signaling and oncogenesis. Furthermore, using global gene expression profiling, we show that GBE-induced HCC exhibit overrepresentation of gene categories associated with human cancer and HCC signaling including upregulation of relevant oncogenes and suppression of critical tumor suppressor genes, as well as chronic oxidative stress, a known inducer of calpain-mediated degradation and promoter of hepatocarcinogenesis in humans. These data provide a molecular mechanism to GBE-induced HCC in B6C3F1 mice that is relevant to human cancer, and provides relevant molecular data that will provide the groundwork for further risk assessment of unregulated compounds, including herbal supplements.

2012-12-07 | GSE29813 | GEO

Genome-wide promoter DNA methylation profiling of hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice.

Project description:Epigenetic modifications, such as DNA methylation, play an important role in carcinogenesis. In a recent NTP study, chronic exposure of B6C3F1/N mice to Ginkgo biloba extract (GBE) resulted in a high incidence of hepatocellular carcinomas (HCC). Genome-wide promoter methylation profiling on GBE-exposed HCC (2000 mg/kg group), spontaneous HCC (vehicle-control group), and age-matched vehicle control liver was performed to identify differentially methylated genes in GBE-exposed HCC and spontaneous HCC. DNA methylation alterations were correlated to the corresponding global gene expression changes. Compared to control liver, 1296 gene promoters (719 hypermethylated, 577 hypomethylated) in GBE-exposed HCC and 738 (427 hypermethylated, 311 hypomethylated) gene promoters in spontaneous HCC were significantly differentially methylated, suggesting an impact of methylation on GBE-exposed HCC. Differential methylation of promoter regions in relevant cancer genes (cMyc, Spry2, Dusp5) and their corresponding differential gene expression was validated by quantitative pyrosequencing and qRT-PCR, respectively. In conclusion, we have identified differentially methylated promoter regions of relevant cancer genes altered in GBE-exposed HCC compared to spontaneous HCC. Further study of unique sets of differentially methylated genes in chemical-exposed mouse HCC could potentially be used to differentiate treatment-related tumors from spontaneous-tumors in cancer bioassays and provide additional understanding of the underlying epigenetic mechanisms of chemical carcinogenesis.

| S-EPMC6830449 | biostudies-literature

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