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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 27, 2011 |
| Title |
Molecular targeting of CSN5 in human hepatocellular carcinoma: a mechanism of therapeutic response |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Development of targeted therapy for hepatocellular carcinoma (HCC) remains a major challenge. We have recently identified an elevated expression of the fifth subunit of COP9 signalosome (CSN5) in early HCC as compared to dysplastic stage. In the present study, we explored the possibility of CSN5 being a potential therapeutic target for HCC. We demonstrate that CSN5 knockdown by small interfering (si) RNA caused a block in cell proliferation and cell cycle progression, and induced apoptosis of HCC cells in vitro. The transcriptomic analysis of CSN5 knockdown signature by microarray showed that the anti-proliferative effect was driven by a common subset of molecular alterations including downregulation of CDK6 or ITGB1, which are involved in cell cycle regulation or tumor invasion and functionally interconnected with key oncogenic regulators such as TGFβ1 and MYC. Western blot assay showed that CSN5 depletion significantly increases the phosphorylation of Smad2/3 and decreases the expression of ITGB1, CDK6 and cyclin D1 proteins, restoring the tumor suppressive function of RB and thereby contributing to inhibition of cell cycle progression. In addition, CSN5 knockdown increased the expression of Bak but decreased the level of Bcl-2, subsequently leading to apoptosis through the activation of caspase-3. A chemically modified variant of CSN5 siRNA was then selected for in vivo application based on the growth inhibitory effect and minimal induction of unwanted immune response. Systemic delivery of the CSN5 3/8 variant by stable-nucleic-acid-lipid-particles (SNALP) significantly suppressed the tumor growth in Huh7-luc+ orthotopic xenograft model. Taken together, these results indicate that CSN5 plays a pivotal role in HCC pathogenesis and maybe an attractive molecular target for systemic HCC therapy.
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| Overall design |
Huh7 and HepG2 cells were treated with CSN5 siRNA and negative control siRNA for 48 hours and subjected to Illumina microarray analysis. 4 replicates each.
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| Contributor(s) |
Lee Y, Seo D, Marquardt JU, Andersen JB, Thorgeirsson SS |
| Citation(s) |
21499307 |
| Submission date |
Jan 06, 2011 |
| Last update date |
Mar 20, 2017 |
| Contact name |
Daekwan Seo |
| E-mail(s) |
daekwan_seo@nih.gov
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| Phone |
301-496-5688
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| Fax |
301-496-0734
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| Organization name |
NIH
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| Department |
NCI
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| Lab |
LEC
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| Street address |
37 Convent Dr. Rm 4140
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20878 |
| Country |
USA |
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| Platforms (1) |
| GPL6883 |
Illumina HumanRef-8 v3.0 expression beadchip |
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| Samples (16)
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| GSM651284 |
Negative Control siRNA, HepG2, rep1 |
| GSM651285 |
Negative Control siRNA, HepG2, rep2 |
| GSM651286 |
Negative Control siRNA, HepG2, rep3 |
| GSM651287 |
Negative Control siRNA, HepG2, rep4 |
| GSM651288 |
CSN5 siRNA, HepG2, rep1 |
| GSM651289 |
CSN5 siRNA, HepG2, rep2 |
| GSM651290 |
CSN5 siRNA, HepG2, rep3 |
| GSM651291 |
CSN5 siRNA, HepG2, rep4 |
| GSM651292 |
Negative Control siRNA, Huh7, rep1 |
| GSM651293 |
Negative Control siRNA, Huh7, rep2 |
| GSM651294 |
Negative Control siRNA, Huh7, rep3 |
| GSM651295 |
Negative Control siRNA, Huh7, rep4 |
| GSM651296 |
CSN5 siRNA, Huh7, rep1 |
| GSM651297 |
CSN5 siRNA, Huh7, rep2 |
| GSM651298 |
CSN5 siRNA, Huh7, rep3 |
| GSM651299 |
CSN5 siRNA, Huh7, rep4 |
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| Relations |
| BioProject |
PRJNA136501 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE26485_RAW.tar |
3.9 Mb |
(http)(custom) |
TAR |
| GSE26485_non-normalized.txt.gz |
3.3 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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