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*


研究成果: 期刊稿件文章同行評審

32 引文 斯高帕斯(Scopus)


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.

頁(從 - 到)6141-6152
期刊Clinical Cancer Research
出版狀態已出版 - 01 12 2014


Publisher Copyright:
© 2014 American Association for Cancer Research.


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