國家衛生研究院 NHRI:Item 3990099045/7953
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    题名: Characterization of the clinical, biological, and therapeutic relevance of EZH2 overexpression in myxofibrosarcoma
    作者: Li, CF;Huang, HY
    贡献者: National Institute of Cancer Research
    摘要: Background: Myxofibrosarcoma is genetically complex and insufficiently characterized in molecular determinants of clinical aggressiveness. By reappraising the public transcriptome (GSE21122), EZH2 was identified as a top-ranking differentially upregulated gene among those regulating chromatin organization (GO:0006325) in myxofibrosarcoma tissues.Design: To validate the pathogenetic role of EZH2 in myxofibrosarcoma, mRNA abundance and protein expression of EZH2 were determined in ndependent samples by branched-chain DNA (bDNA) and immunohistochemical assays, yielding 40 and 87 informative cases, respectively. In vitro, RNA interference and DZNep treatment (targeting EZH2 associated PRC2 complex) were applied in EZH2-expressing myxofibrosarcoma cell lines to evaluate for the biological functions and therapeutic relevance of EZH2. The in vivo effect of DZNep treatment was examined in xenograft models established from two myxofibrosarcoma cell lines.Results: EZH2 protein overexpression was associated with higher histological grade (p=0.002), worse disease-specific and metastasis-free survival (both p£0.0001), and mRNA upregulation (p=0.010). In all myxofi brosarcoma cell lines, stable EZH2 knockdown resulted in impaired cell proliferative, migratory, and invasive capabilities with concomitant reductions in anchorage-independent colony formation and well-formed endothelial tubes. In vitro, DZNep caused dose- and time-dependent cytotoxicity and downregulated PRC2-associated proteins with induction of cellular apoptosis and attenuation of EZH2 promoter transactivity. The dose-dependent therapeutic efficacy of DZNep was further corroborated in vivo in both xenograft myxofi brosarcoma models.Conclusions: EZH2 overexpression plays an oncogenic role in myxofibrosarcoma pathogenesis and promotes tumor growth, migration/invasion, and angiogenesis, hence conferring clinical aggressiveness and representing a novel therapeutic target of DZNep therapy.
    日期: 2014-02
    關聯: Laboratory Investigation. 2014 Feb;94(S1):22A.
    Link to: http://dx.doi.org/10.1038/labinvest.2014.15
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0023-6837&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000331155800075
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