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Molecular targeting of CSN5 in human hepatocellular carcinoma: a mechanism of therapeutic response.

ABSTRACT: 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 with dysplastic stage. In the present study, we explored the possibility of CSN5 being a potential therapeutic target for HCC. Our results show that CSN5 knockdown by small-interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell-cycle progression in HCC cells in vitro. The down-regulation of CSN5 was sufficient to interfere with CSN function as evidenced by the accumulation of neddylated Cullin 1 and changes in the protein levels of CSN-controlled substrates SKP2, p53, p27 and nuclear factor-?B, albeit to a different degree depending on the HCC cell line, which could account for the CSN5 knockdown phenotype. The transcriptomic analysis of CSN5 knockdown signature showed that the anti-proliferative effect was driven by a common subset of molecular alterations including down-regulation of cyclin-dependent kinase 6 (CDK6) and integrin ?1 (ITGB1), which were functionally interconnected with key oncogenic regulators MYC and TGF?1 involved in the control of proliferation, apoptotic cell death and HCC progression. Consistent with microarray analysis, western blotting revealed that CSN5 depletion increased phosphorylation of Smad 2/3, key mediators of TGF?1 signaling, decreased the protein levels of ITGB1, CDK6 and cyclin D1 and caused reduced expression of anti-apoptotic Bcl-2, while elevating the levels of pro-apoptotic Bak. 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 significantly suppressed the tumor growth in Huh7-luc+ orthotopic xenograft model. Taken together, these results indicate that CSN5 has a pivotal role in HCC pathogenesis and maybe an attractive molecular target for systemic HCC therapy.

SUBMITTER: Lee YH

PROVIDER: S-EPMC3140552 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Molecular targeting of CSN5 in human hepatocellular carcinoma: a mechanism of therapeutic response.

Lee Y-H YH Judge A D AD Seo D D Kitade M M Gómez-Quiroz L E LE Ishikawa T T Andersen J B JB Kim B-K BK Marquardt J U JU Raggi C C Avital I I Conner E A EA MacLachlan I I Factor V M VM Thorgeirsson S S SS

Oncogene 20110418 40

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 with dysplastic stage. In the present study, we explored the possibility of CSN5 being a potential therapeutic target for HCC. Our results show that CSN5 knockdown by small-interfering (si) RNA caused a strong induction of apoptosis and inhibition of cell-cycle progression in HCC c ...[more]

PMID: 21499307

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Project description: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. 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.

Project description:BackgroundHepatocellular carcinoma (HCC) is a highly prevalent and fatal cancer. The role of PANoptosis, a novel form of programmed cell death, in HCC is yet to be fully understood. This study focuses on identifying and analyzing PANoptosis-associated differentially expressed genes in HCC (HPAN_DEGs), aiming to enhance our understanding of HCC pathogenesis and potential treatment strategies.MethodsWe analyzed HCC differentially expressed genes from TCGA and IGCG databases and mapped them to the PANoptosis gene set, identifying 69 HPAN_DEGs. These genes underwent enrichment analyses, and consensus clustering analysis was used to determine three distinct HCC subgroups based on their expression profiles. The immune characteristics and mutation landscape of these subgroups were evaluated, and drug sensitivity was predicted using the HPAN-index and relevant databases.ResultsThe HPAN_DEGs were mainly enriched in pathways associated with the cell cycle, DNA damage, Drug metabolism, Cytokines, and Immune receptors. We identified three HCC subtypes (Cluster_1, SFN+PDK4-; Cluster_2, SFN-PDK4+; Cluster_3, SFN/PDK4 intermediate expression) based on the expression profiles of the 69 HPAN_DEGs. These subtypes exhibited distinct clinical outcomes, immune characteristics, and mutation landscapes. The HPAN-index, generated by machine learning using the expression levels of 69 HPAN_DEGs, was identified as an independent prognostic factor for HCC. Moreover, the high HPAN-index group exhibited a high response to immunotherapy, while the low HPAN-index group showed sensitivity to small molecule targeted drugs. Notably, we observed that the YWHAB gene plays a significant role in Sorafenib resistance.ConclusionThis study identified 69 HPAN_DEGs crucial to tumor growth, immune infiltration, and drug resistance in HCC. Additionally, we discovered three distinct HCC subtypes and constructed an HPAN-index to predict immunotherapeutic response and drug sensitivity. Our findings underscore the role of YWHAB in Sorafenib resistance, presenting valuable insights for personalized therapeutic strategy development in HCC.

Dataset Information

Molecular targeting of CSN5 in human hepatocellular carcinoma: a mechanism of therapeutic response.

Publications

Molecular targeting of CSN5 in human hepatocellular carcinoma: a mechanism of therapeutic response.

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