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Identification of genes conferring resistance to 5-fluorouracil
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Identification of genes conferring resistance to 5-fluorouracil
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Identification of genes conferring resistance to 5-fluorouracil
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Journal Article
Identification of genes conferring resistance to 5-fluorouracil
2009
Overview
Astrocyte elevated gene-1 (AEG-1) is overexpressed in >90% of human hepatocellular carcinoma (HCC) patients and plays a significant role in mediating aggressive progression of HCC. AEG-1 is known to augment invasion, metastasis, and angiogenesis, and we now demonstrate that AEG-1 directly contributes to another important hallmark of aggressive cancers, that is, resistance to chemotherapeutic drugs, such as 5-fluorouracil (5-FU). AEG-1 augments expression of the transcription factor LSF that regulates the expression of thymidylate synthase (TS), a target of 5-FU. In addition, AEG-1 enhances the expression of dihydropyrimidine dehydrogenase (DPYD) that catalyzes the initial and rate-limiting step in the catabolism of 5-FU. siRNA-mediated inhibition of AEG-1, LSF, or DPYD significantly increased the sensitivity of HCC cells to 5-FU in vitro and a lentivirus delivering AEG-1 siRNA in combination with 5-FU markedly inhibited growth of HCC cells xenotransplanted in athymic nude mice when compared to either agent alone. The present studies highlight 2 previously unidentified genes, AEG-1 and LSF, contributing to chemoresistance. Inhibition of AEG-1 might be exploited as a therapeutic strategy along with 5-FU-based combinatorial chemotherapy for HCC, a highly fatal cancer with currently very limited therapeutic options.
Publisher
National Academy of Sciences,National Acad Sciences
Subject
/ Animals
/ Antimetabolites, Antineoplastic - pharmacology
/ Cancer
/ Carcinoma, Hepatocellular - drug therapy
/ Carcinoma, Hepatocellular - genetics
/ Cell Adhesion Molecules - antagonists & inhibitors
/ Cell Adhesion Molecules - genetics
/ Cells
/ Dihydrouracil Dehydrogenase (NADP) - physiology
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - physiology
/ Drug Resistance, Neoplasm - genetics
/ Genes
/ hepatoma
/ Humans
/ Liver Neoplasms - drug therapy
/ Mice
/ patients
/ Rodents
/ siRNA
/ Thymidylate Synthase - genetics
/ Transcription Factors - genetics
/ Transcription Factors - physiology
/ Tumors
