Identification of genes conferring resistance to 5-fluorouracil

Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12938-43. doi: 10.1073/pnas.0901451106. Epub 2009 Jul 21.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / genetics
  • Cell Adhesion Molecules / antagonists & inhibitors
  • Cell Adhesion Molecules / genetics*
  • Cell Line, Tumor
  • DNA / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology
  • Dihydrouracil Dehydrogenase (NADP) / physiology
  • Drug Resistance, Neoplasm / genetics
  • Fluorouracil / pharmacology*
  • Humans
  • Ki-67 Antigen / analysis
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Membrane Proteins
  • Mice
  • RNA-Binding Proteins
  • Thymidylate Synthase / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / physiology


  • Antimetabolites, Antineoplastic
  • Cell Adhesion Molecules
  • DNA-Binding Proteins
  • Ki-67 Antigen
  • MTDH protein, human
  • Membrane Proteins
  • RNA-Binding Proteins
  • TFCP2 protein, human
  • Transcription Factors
  • DNA
  • Dihydrouracil Dehydrogenase (NADP)
  • Thymidylate Synthase
  • Fluorouracil