Definition of ubiquitination modulator COP1 as a novel therapeutic target in human hepatocellular carcinoma.
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.
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA.
Yun-Han
YH
Lee
Jesper B
JB
Andersen
Ho-Taek
HT
Song
Adam D
AD
Judge
Daekwan
D
Seo
Tsuyoshi
T
Ishikawa
Jens U
JU
Marquardt
Mitsuteru
M
Kitade
Marian E
ME
Durkin
Chiara
C
Raggi
Hyun Goo
HG
Woo
Elizabeth A
EA
Conner
Itzhak
I
Avital
Ian
I
Maclachlan
Valentina M
VM
Factor
Snorri S
SS
Thorgeirsson
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D002453:Cell Cycle; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C471981:COP1 protein, human; D044767:Ubiquitin-Protein Ligases