Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma

Potential implications in tumor progression and therapeutics

Chien Feng Li, Ju-Ming Wang, Hong Yo Kang, Chiung Kuei Huang, Jun Wen Wang, Fu Min Fang, Yu Hui Wang, Wen Ren Wu, Shau Hsuan Li, Shih Chen Yu, Jen Chieh Lee, Jui Lan, Yow Ling Shiue, Li Ching Wu, Hsuan Ying Huang

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification. Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib. Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2- expressing OH931cells and14% of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27 kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27 kip1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target.

Original languageEnglish
Pages (from-to)1598-1610
Number of pages13
JournalClinical Cancer Research
Volume18
Issue number6
DOIs
Publication statusPublished - 2012 Mar 15

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Gene Amplification
Neoplasms
Down-Regulation
Genes
Therapeutics
Messenger RNA
Comparative Genomic Hybridization
Gene Dosage
DNA Nucleotidylexotransferase
Proteasome Endopeptidase Complex
Growth
Caspases
Ubiquitin
Heterografts
Sarcoma
Cell Movement
Cell Survival
Research Design
Fibroblasts
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Li, Chien Feng ; Wang, Ju-Ming ; Kang, Hong Yo ; Huang, Chiung Kuei ; Wang, Jun Wen ; Fang, Fu Min ; Wang, Yu Hui ; Wu, Wen Ren ; Li, Shau Hsuan ; Yu, Shih Chen ; Lee, Jen Chieh ; Lan, Jui ; Shiue, Yow Ling ; Wu, Li Ching ; Huang, Hsuan Ying. / Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma : Potential implications in tumor progression and therapeutics. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 6. pp. 1598-1610.
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abstract = "Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification. Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib. Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38{\%} of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2- expressing OH931cells and14{\%} of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27 kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27 kip1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target.",
author = "Li, {Chien Feng} and Ju-Ming Wang and Kang, {Hong Yo} and Huang, {Chiung Kuei} and Wang, {Jun Wen} and Fang, {Fu Min} and Wang, {Yu Hui} and Wu, {Wen Ren} and Li, {Shau Hsuan} and Yu, {Shih Chen} and Lee, {Jen Chieh} and Jui Lan and Shiue, {Yow Ling} and Wu, {Li Ching} and Huang, {Hsuan Ying}",
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Li, CF, Wang, J-M, Kang, HY, Huang, CK, Wang, JW, Fang, FM, Wang, YH, Wu, WR, Li, SH, Yu, SC, Lee, JC, Lan, J, Shiue, YL, Wu, LC & Huang, HY 2012, 'Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma: Potential implications in tumor progression and therapeutics', Clinical Cancer Research, vol. 18, no. 6, pp. 1598-1610. https://doi.org/10.1158/1078-0432.CCR-11-3077

Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma : Potential implications in tumor progression and therapeutics. / Li, Chien Feng; Wang, Ju-Ming; Kang, Hong Yo; Huang, Chiung Kuei; Wang, Jun Wen; Fang, Fu Min; Wang, Yu Hui; Wu, Wen Ren; Li, Shau Hsuan; Yu, Shih Chen; Lee, Jen Chieh; Lan, Jui; Shiue, Yow Ling; Wu, Li Ching; Huang, Hsuan Ying.

In: Clinical Cancer Research, Vol. 18, No. 6, 15.03.2012, p. 1598-1610.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Characterization of gene amplification-driven SKP2 overexpression in myxofibrosarcoma

T2 - Potential implications in tumor progression and therapeutics

AU - Li, Chien Feng

AU - Wang, Ju-Ming

AU - Kang, Hong Yo

AU - Huang, Chiung Kuei

AU - Wang, Jun Wen

AU - Fang, Fu Min

AU - Wang, Yu Hui

AU - Wu, Wen Ren

AU - Li, Shau Hsuan

AU - Yu, Shih Chen

AU - Lee, Jen Chieh

AU - Lan, Jui

AU - Shiue, Yow Ling

AU - Wu, Li Ching

AU - Huang, Hsuan Ying

PY - 2012/3/15

Y1 - 2012/3/15

N2 - Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification. Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib. Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2- expressing OH931cells and14% of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27 kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27 kip1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target.

AB - Purpose: Myxofibrosarcoma remains obscure in molecular determinants of clinical aggressiveness, for which we elucidated implications of SKP2 amplification. Experimental Design: Array comparative genomic hybridization was applied on samples and cell lines (NMFH-1 to OH931) to search causal genes of tumor progression. SKP2 gene dosage was determined in 82 independent tumors for clinical correlates. Stable SKP2 knockdown was achieved in myxofibrosarcoma cells to assess its oncogenic attributes and candidate mediators in prometastatic function. Pharmacologic assays were evaluated in vitro and in vivo for the therapeutic relevance of bortezomib. Results: DNA gains frequently involved 5p in which three amplicons were differentially overrepresented in samples behaving unfavorably, encompassing mRNA-upregulated TRIO, SKP2, and AMACR genes. Detected in NMFH-1 cells and 38% of tumors, SKP2 amplification was associated with SKP2 immunoexpression and adverse prognosticators and independently predictive of worse outcomes. Nevertheless, SKP2- expressing OH931cells and14% of such tumors lacked gene amplification. Knockdown of SKP2 suppressed proliferation, anchorage-independent growth, migration, and invasion of sarcoma cells and downregulated motility-promoting genes, including ITGB2, ACTN1, IGF1, and ENAH. In vitro, bortezomib downregulated SKP2 expression at the mRNA level with p27 kip1 accumulation, induced caspase activation, and decreased cell viability in myxofibrosarcoma cells but not in fibroblasts. In vivo, bortezomib inhibited growth of NMFH-1 xenografts, the cells of which displayed decreased SKP2 expression but increased p27 kip1 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Conclusions: As a predominant mechanism driving protein overexpression, SKP2 amplification confers tumor aggressiveness in myxofibrosarcoma. The sensitivity of myxofibrosarcoma cells to bortezomib with SKP2-repressing effect indicates the potentiality of ubiquitin-proteasome pathway as a therapeutic target.

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