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 (US)
Pages (from-to)6141-6152
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number23
DOIs
StatePublished - 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

  • Cancer Research
  • Oncology

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, H-J, 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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