AMACR amplification in myxofibrosarcomas: A mechanism of overexpression that promotes cell proliferation with therapeutic relevance

Chien Feng Li, Fu Min Fang, Jui Lan, Jun Wen Wang, Hsing Jien Kung, Li Tzong Chen, Tzu Ju Chen, Shau Hsuan Li, Yu Hui Wang, Hui Chun Tai, Shih Chen Yu, Hsuan Ying Huang

Research output: Contribution to journalArticle

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Abstract

Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the α-methylacyl coenzyme A racemase (AMACR) at 5p13.3.

Experimental Design: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed florescence in situ hybridization (FISH) and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpres-sing myxofibrosarcoma cells and xenografts, we elucidated the biologic function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide.

Results: AMACR protein overexpression and gene amplification were significantly associated with each other (P < 0.001), with higher tumor grades (both P < 0.002), and univariately with worse metastasis-free survival (MFS; both P < 0.0001) and disease-specific survival (DSS; P - 0.0002 for overexpression; P - 0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, P - 0.007; MFS, P - 0.001). However, 39% of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared with fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to ebselen oxide, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro, but also dose-dependently suppressed xenografted tumor growth in vivo.

Conclusions: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and maybe relevant as a druggable target.

Original languageEnglish
Pages (from-to)6141-6152
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number23
DOIs
Publication statusPublished - Dec 1 2014
Externally publishedYes

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Cyclin T
Cell Proliferation
Gene Amplification
Cyclin D1
Heterografts
Oxides
Growth
Racemases and Epimerases
Neoplasms
Therapeutic Uses
Proteasome Endopeptidase Complex
Coenzyme A
Therapeutics
RNA Interference
Transcriptome
Sarcoma
Proteolysis
In Situ Hybridization
Proteins
Lasers

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

AMACR amplification in myxofibrosarcomas : A mechanism of overexpression that promotes cell proliferation with therapeutic relevance. / Li, Chien Feng; Fang, Fu Min; Lan, Jui; Wang, Jun Wen; Kung, Hsing Jien; Chen, Li Tzong; Chen, Tzu Ju; Li, Shau Hsuan; Wang, Yu Hui; Tai, Hui Chun; Yu, Shih Chen; Huang, Hsuan Ying.

In: Clinical Cancer Research, Vol. 20, No. 23, 01.12.2014, p. 6141-6152.

Research output: Contribution to journalArticle

Li, CF, Fang, FM, Lan, J, Wang, JW, Kung, HJ, Chen, LT, Chen, TJ, Li, SH, Wang, YH, Tai, HC, Yu, SC & Huang, HY 2014, 'AMACR amplification in myxofibrosarcomas: A mechanism of overexpression that promotes cell proliferation with therapeutic relevance', Clinical Cancer Research, vol. 20, no. 23, pp. 6141-6152. https://doi.org/10.1158/1078-0432.CCR-14-1182
Li, Chien Feng ; Fang, Fu Min ; Lan, Jui ; Wang, Jun Wen ; Kung, Hsing Jien ; Chen, Li Tzong ; Chen, Tzu Ju ; Li, Shau Hsuan ; Wang, Yu Hui ; Tai, Hui Chun ; Yu, Shih Chen ; Huang, Hsuan Ying. / AMACR amplification in myxofibrosarcomas : A mechanism of overexpression that promotes cell proliferation with therapeutic relevance. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 23. pp. 6141-6152.
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abstract = "Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the α-methylacyl coenzyme A racemase (AMACR) at 5p13.3.Experimental Design: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed florescence in situ hybridization (FISH) and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpres-sing myxofibrosarcoma cells and xenografts, we elucidated the biologic function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide.Results: AMACR protein overexpression and gene amplification were significantly associated with each other (P < 0.001), with higher tumor grades (both P < 0.002), and univariately with worse metastasis-free survival (MFS; both P < 0.0001) and disease-specific survival (DSS; P - 0.0002 for overexpression; P - 0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, P - 0.007; MFS, P - 0.001). However, 39{\%} of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared with fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to ebselen oxide, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro, but also dose-dependently suppressed xenografted tumor growth in vivo.Conclusions: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and maybe relevant as a druggable target.",
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T1 - AMACR amplification in myxofibrosarcomas

T2 - A mechanism of overexpression that promotes cell proliferation with therapeutic relevance

AU - Li, Chien Feng

AU - Fang, Fu Min

AU - Lan, Jui

AU - Wang, Jun Wen

AU - Kung, Hsing Jien

AU - Chen, Li Tzong

AU - Chen, Tzu Ju

AU - Li, Shau Hsuan

AU - Wang, Yu Hui

AU - Tai, Hui Chun

AU - Yu, Shih Chen

AU - Huang, Hsuan Ying

PY - 2014/12/1

Y1 - 2014/12/1

N2 - Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the α-methylacyl coenzyme A racemase (AMACR) at 5p13.3.Experimental Design: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed florescence in situ hybridization (FISH) and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpres-sing myxofibrosarcoma cells and xenografts, we elucidated the biologic function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide.Results: AMACR protein overexpression and gene amplification were significantly associated with each other (P < 0.001), with higher tumor grades (both P < 0.002), and univariately with worse metastasis-free survival (MFS; both P < 0.0001) and disease-specific survival (DSS; P - 0.0002 for overexpression; P - 0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, P - 0.007; MFS, P - 0.001). However, 39% of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared with fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to ebselen oxide, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro, but also dose-dependently suppressed xenografted tumor growth in vivo.Conclusions: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and maybe relevant as a druggable target.

AB - Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the α-methylacyl coenzyme A racemase (AMACR) at 5p13.3.Experimental Design: AMACR mRNA expression in myxofibrosarcomas was analyzed using the public transcriptome and laser-microdissected sarcoma cells. We performed florescence in situ hybridization (FISH) and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpres-sing myxofibrosarcoma cells and xenografts, we elucidated the biologic function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide.Results: AMACR protein overexpression and gene amplification were significantly associated with each other (P < 0.001), with higher tumor grades (both P < 0.002), and univariately with worse metastasis-free survival (MFS; both P < 0.0001) and disease-specific survival (DSS; P - 0.0002 for overexpression; P - 0.0062 for amplification). AMACR protein overexpression also independently portended adverse outcome (DSS, P - 0.007; MFS, P - 0.001). However, 39% of AMACR-overexpression cases did not show gene amplification, implying alternative regulatory mechanisms. In myxofibrosarcoma cell lines, stable AMACR knockdown suppressed cell proliferation, anchorage-independent growth, and expression of cyclin D1 and cyclin T2. These growth-promoting attributes of AMACR were corroborated in the AMACR-silenced xenograft model and AMACR-underexpressed myxofibrosarcomas, showing decreased labeling for cyclin D1, cyclin T2, and Ki-67. Compared with fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to ebselen oxide, which not only decreased viable cells, promoted proteasome-mediated degradation of AMACR protein, and induced cellular apoptosis in vitro, but also dose-dependently suppressed xenografted tumor growth in vivo.Conclusions: Overexpressed AMACR in myxofibrosarcomas can be amplification-driven, associated with tumor aggressiveness, and maybe relevant as a druggable target.

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