國家衛生研究院 NHRI:Item 3990099045/8146
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    題名: Clinical aggressiveness of myxofibrosarcomas associates with down-regulation of p12cdk2ap1: Prognostic implication of a putative tumor suppressor that induces cell cycle arrest and apoptosis via mitochondrial pathway
    作者: Li, CF;Huang, HY;Wu, WR;Liang, SS;Chen, YL;Chen, LR;Peng, YT;Lee, HC;Shiue, YL
    貢獻者: National Institute of Cancer Research
    摘要: Background Attenuated endogenous protein levels of cyclin-dependent kinase 2 associated protein 1 (p12CDK2AP1) and its active homodimer p25CDK2AP1 were found in myxofibrosarcoma-derived cell lines. Clinical and biological significances of this putative tumor suppressor in myxofibrosarcoma were studied. Methods Plasmids carrying the CDK2AP1 gene and small hairpin RNA interference (shRNAi) targeting CDK2AP1 were transfected into NMFH-1 and/or OH931 cells to evaluate the effects on the CDK2, active caspase 3 (CASP3), cleaved-CASP8 and -CASP9 levels, cell cycle regulation, and/or apoptotic responses. Immunostaining of p12CDK2AP1 was interpretable in 102 primary myxofibrosarcomas and correlated with clinicopathological variables, CDK2, Ki-67 and active CASP3 protein levels, and disease-specific survival. Results Exogenous expression of p12CDK2AP1 in NMFH-1 and OH931 cells significantly induced G0/G1 cell cycle arrest and down-regulated CDK2 protein level. In NMFH-1 cells, these aspects were reversed by shRNAi targeting CDK2AP1 gene. Increased active CASP3 and cleaved-CASP9, but not -CASP8, were detected after CDK2AP1 overexpression, suggesting the cellular apoptosis were induced through the mitochondrial pathway. Immunostains of p12CDK2AP1 were aberrantly decreased in 56.9 % of cases; positively and negatively correlated with protein levels of CDK2 (p = 0.023), Ki-67 (p = 0.001) and active CASP3 (p < 0.001), respectively. Following by high histological grades, p12CDK2AP1 down-regulation was predictive of worse disease-specific survival in univariate (p = 0.003) and multivariate (p = 0.004) analyses. Conclusions Through down-regulation of CDK2, high p12CDK2AP1 level induced cell cycle arrest and the mitochondrial-dependent apoptotic pathway. Low p12CDK2AP1 level represents a poor prognostic factor in patients with myxofibrosarcoma.
    日期: 2014-12
    關聯: Annals of Surgical Oncology. 2014 Dec;21(4 Suppl.):711-720.
    Link to: http://dx.doi.org/10.1245/s10434-014-3825-0
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1068-9265&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000345320300040
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84939887546
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