RRC ID 38142
著者 Andersen JB, Factor VM, Marquardt JU, Raggi C, Lee YH, Seo D, Conner EA, Thorgeirsson SS.
タイトル An integrated genomic and epigenomic approach predicts therapeutic response to zebularine in human liver cancer.
ジャーナル Sci Transl Med
Abstract Epigenomic changes such as aberrant hypermethylation and subsequent atypical gene silencing are characteristic features of human cancer. Here, we report a comprehensive characterization of epigenomic modulation caused by zebularine, an effective DNA methylation inhibitor, in human liver cancer. Using transcriptomic and epigenomic profiling, we identified a zebularine response signature that classified liver cancer cell lines into two major subtypes with different drug responses. In drug-sensitive cell lines, zebularine caused inhibition of proliferation coupled with increased apoptosis, whereas drug-resistant cell lines showed up-regulation of oncogenic networks (for example, E2F1, MYC, and TNF) that drive liver cancer growth in vitro and in preclinical mouse models. Assessment of zebularine-based therapy in xenograft mouse models demonstrated potent therapeutic effects against tumors established from zebularine-sensitive but not zebularine-resistant liver cancer cells, leading to increased survival and decreased pulmonary metastasis. Integration of the zebularine gene expression and demethylation response signatures allowed differentiation of patients with hepatocellular carcinoma according to their survival and disease recurrence. This integrated signature identified a subclass of patients within the poor-survivor group that is likely to benefit from therapeutic agents that target the cancer epigenome.
巻・号 2(54)
ページ 54ra77
公開日 2010-10-20
DOI 10.1126/scitranslmed.3001338
PII 2/54/54ra77
PMID 20962331
PMC PMC3077922
MeSH Animals Antineoplastic Agents / therapeutic use* Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / pathology Cell Line, Tumor CpG Islands Cytidine / analogs & derivatives* Cytidine / therapeutic use DNA Methylation Epigenesis, Genetic* Gene Expression Profiling Genome, Human* Humans Liver Neoplasms / drug therapy* Liver Neoplasms / genetics Liver Neoplasms / pathology Mice Transplantation, Heterologous
IF 16.304
引用数 82
WOS 分野 MEDICINE, RESEARCH & EXPERIMENTAL CELL BIOLOGY
リソース情報
ヒト・動物細胞 HuH-7(RCB1366)