title: Identification of genes conferring resistance to 5-fluorouracil.
abstract: 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.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Rachel
authors.initials: R
authors.lastname: Gredler
authors.forename: Nicollaq
authors.initials: N
authors.lastname: Vozhilla
authors.forename: Zao-zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.forename: Talitha
authors.initials: T
authors.lastname: Forcier
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
authors.forename: Utsav
authors.initials: U
authors.lastname: Saxena
authors.forename: Ulla
authors.initials: U
authors.lastname: Hansen
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D016601:RNA-Binding Proteins; D013940:Thymidylate Synthase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: D000964:Antimetabolites, Antineoplastic; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; C501906:TFCP2 protein, human; D014157:Transcription Factors; D004247:DNA; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil