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Definition of Ubiquitination Modulator COP1 as a Novel Therapeutic Target in Human Hepatocellular Carcinoma

Authors
 Yun-Han Lee  ;  Jesper B. Andersen  ;  Ho-Taek Song  ;  Adam D. Judge  ;  Daekwan Seo  ;  Tsuyoshi Ishikawa  ;  Jens U. Marquardt  ;  Mitsuteru Kitade  ;  Marian Durkin1, Chiara Raggi  ;  Hyun Goo Woo  ;  Elizabeth A. Conner  ;  Itzhak Avital  ;  Ian MacLachlan  ;  Valentina M. Factor  ;  Snorri S. Thorgeirsson 
Citation
 CANCER RESEARCH, Vol.70(21) : 8264-8269, 2010 
Journal Title
 CANCER RESEARCH 
ISSN
 0008-5472 
Issue Date
2010
MeSH
Animals ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Blotting, Western ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism* ; Carcinoma, Hepatocellular/prevention & control* ; Cell Cycle ; Gene Expression Profiling ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism* ; Liver Neoplasms/prevention & control* ; Male ; Mice ; Mice, SCID ; Mutation/genetics ; Oligonucleotide Array Sequence Analysis ; RNA, Messenger/genetics ; RNA, Small Interfering/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Transplantation, Heterologous ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin/metabolism* ; Ubiquitin-Protein Ligases/antagonists & inhibitors ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism* ; Ubiquitination
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.
Files in This Item:
T201006075.pdf Download
DOI
10.1158/0008-5472.CAN-10-0749
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Song, Ho Taek(송호택) ORCID logo https://orcid.org/0000-0002-6655-2575
Lee, Yun Han(이윤한)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/103300
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