Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: NIEHS Microarray Core

PROVIDER: E-GEOD-29813 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Hepatocellular carcinomas in B6C3F1 mice treated with Ginkgo biloba extract for two years differ from spontaneous liver tumors in cancer gene mutations and genomic pathways.

Hoenerhoff Mark J MJ Pandiri Arun R AR Snyder Stephanie A SA Hong Hue-Hua L HH Ton Thai-Vu TV Peddada Shyamal S Shockley Keith K Witt Kristine K Chan Po P Rider Cynthia C Kooistra Linda L Nyska Abraham A Sills Robert C RC

Toxicologic pathology 20121221 6

Ginkgo biloba leaf extract (GBE) has been used for centuries in traditional Chinese medicine and today is used as an herbal supplement touted for improving neural function and for its antioxidant and anticancer effects. Herbal supplements have the potential for consumption over extended periods of time, with a general lack of sufficient data on long-term carcinogenicity risk. Exposure of B6C3F1 mice to GBE in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-depe ...[more]

PMID: 23262642

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Project description:Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, where sorafenib, a multiple target ty-rosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of the treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying to sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) da-tabase was utilised through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide met-abolic pathways, energy production pathways and other pathways related to cancer aggressive-ness, migration, proliferation, and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified po-tential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression, and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

Dataset Information

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

Publications

Hepatocellular carcinomas in B6C3F1 mice treated with Ginkgo biloba extract for two years differ from spontaneous liver tumors in cancer gene mutations and genomic pathways.

Similar Datasets

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