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http://ir.nhri.org.tw/handle/3990099045/8418
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| Title: | AMACR amplification in myxofibrosarcomas: A mechanism of overexpression that promotes cell proliferation with therapeutic relevance |
| Authors: | Li, CF;Fang, FM;Lan, J;Wang, JW;Kung, HJ;Chen, LT;Chen, TJ;Li, SH;Wang, YH;Tai, HC;Yu, SC;Huang, HY |
| Contributors: | National Institute of Cancer Research;Institute of Molecular and Genomic Medicine |
| Abstract: | Purpose: Myxofibrosarcomas frequently display arm-level gains on 5p. We characterized the pathogenetic and therapeutic relevance of the alpha-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 FISH and immunohistochemistry in independent samples for clinical correlates. In AMACR-overexpressing myxofibrosarcoma cells and xenografts, we elucidated the biological function of AMACR using RNA interference and explored the therapeutic effect and mechanism of an AMACR inhibitor, ebselen oxide (EO). 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 to fibroblasts, AMACR-expressing myxofibrosarcoma cells were more susceptible to EO, 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 may be relevant as a druggable target. |
| Date: | 2014-12-01 |
| Relation: | Clinical Cancer Research. 2014 Dec 01;20(23):6141-6152. |
| Link to: | http://dx.doi.org/10.1158/1078-0432.ccr-14-1182 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1078-0432&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000346417400030 |
| Cited Times(Scopus): | http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84918544789 |
| Appears in Collections: | [陳立宗] 期刊論文
[龔行健] 期刊論文
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| PUB25384383.pdf | | 3452Kb | Adobe PDF | 557 | View/Open |
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