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Definition of ubiquitination modulator COP1 as a novel therapeutic target in human hepatocellular carcinoma.

Authors
Lee, YH; Andersen, JB; Song, HT; Judge, AD; Seo, D; Ishikawa, T; Marquardt, JU; Kitade, M; Durkin, ME; Raggi, C; Woo, HG; Conner, EA; Avital, I; Maclachlan, I; Factor, VM; Thorgeirsson, SS
Citation
Cancer research, 70(21):8264-8269, 2010
Journal Title
Cancer research
ISSN
0008-54721538-7445
Abstract
The development of targeted therapeutics for hepatocellular carcinoma (HCC) remains a major challenge. The ubiquitination modulator COP1 regulates p53 activity by ubiquitination and it is frequently overexpressed in human HCC. In this study, we tested the hypothesis that COP1 blockade by short interfering RNA (siRNA)-mediated inhibition could affect the course of HCC progression. The COP1 isoform COP1-1 was selected as the most effective target for siRNAs in terms of growth inhibition and apoptotic induction in several HCC cell lines. Growth inhibition occurred in HCC cells that retained wild-type p53 or expressed mutant p53 (Y220C or R249S), whereas p53-null Hep3B cells were resistant. Microarray expression analysis revealed that the antiproliferative effects of COP1 blockade were driven by a common subset of molecular alterations including a p53-associated functional network. In an orthotopic mouse xenograft model of HCC, systemic delivery of a modified COP1 siRNA by stable nucleic acid-lipid particles suppressed neoplastic growth in liver without unwanted immune responses. Our findings offer a first proof of principle that COP1 can be a promising target for systemic therapy of HCC.
MeSH terms
AnimalsBlotting, WesternCarcinoma, Hepatocellular/geneticsCarcinoma, Hepatocellular/metabolism*Carcinoma, Hepatocellular/prevention & control*Cell CycleGene Expression ProfilingHumansLiver Neoplasms/geneticsLiver Neoplasms/metabolism*Liver Neoplasms/prevention & control*MaleMiceMice, SCIDMutation/geneticsOligonucleotide Array Sequence AnalysisRNA, Messenger/geneticsRNA, Small Interfering/pharmacologyReverse Transcriptase Polymerase Chain ReactionTransplantation, HeterologousTumor Cells, CulturedTumor Markers, Biological/geneticsTumor Markers, Biological/metabolismTumor Suppressor Protein p53/geneticsTumor Suppressor Protein p53/metabolismUbiquitin/metabolism*Ubiquitin-Protein Ligases/antagonists & inhibitorsUbiquitin-Protein Ligases/geneticsUbiquitin-Protein Ligases/metabolism*Ubiquitination
DOI
10.1158/0008-5472.CAN-10-0749
PMID
20959491
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
AJOU Authors
우, 현구
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