TMPRSS2/ERG Fusion Gene Expression Alters Chemo- and Radio-Responsiveness in Cell Culture Models of Androgen Independent Prostate Cancer
TMPRSS2/ERG Fusion Gene Expression Alters Chemo- and Radio-Responsiveness in Cell Culture Models of Androgen Independent Prostate Cancer
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DOI：
10.1002/pros.21371
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发表时间：
2011-10-01
期刊：
影响因子：
2.8
通讯作者：
Marples, Brian
中科院分区：
文献类型：
--
作者：
Swanson, Todd A.;Krueger, Sarah A.;Marples, Brian
目的/目标。雄激素调节的跨膜丝氨酸蛋白酶(TMPRSS2)和ETS转录因子(ERG)基因融合是预测前列腺癌术后复发的重要预后因素。TMPRSS2/ETS相关基因(ERG)融合基因转录本的表达与肿瘤的增殖、侵袭和侵袭性表型有关。本研究的目的是确定TMPRSS2/ERG融合基因表达对前列腺癌细胞株化疗和放射敏感性的影响。检测X射线照射(0~8GyX射线)和紫杉醇对稳定表达TMPRSS2/ERGⅢ和VI型融合基因的PC3和DU145细胞的克隆存活率。观察细胞周期变化及DNA双链断裂诱导和修复情况。采用基因芯片技术检测差异基因表达。结果TMPRSS2/ERG融合基因在PC3细胞中的表达增加了细胞对辐射的敏感性，降低了紫杉醇的敏感性。辐射敏感性的提高与辐射后24小时持续的DNA断裂、DNA修复和有丝分裂相关基因的下调以及ETS转录因子ETV的上调有关。然而，DU145III型和VI型表现出不同的敏感性表型和基因表达变化。ERG信号通路分析进一步揭示了含TMPRSS2/ERG融合基因的PC3和DU145细胞系之间的差异。结论TMPRSS2/ERG基因融合对放射敏感性和化疗敏感性的影响因细胞系和融合类型不同而不同。需要对临床样本进行进一步的研究，以确定TMPRSS2/ERG基因融合是否会影响体内的放射和化疗敏感性。前列腺癌71：1548-1558,2011。(C)2011年Wiley-Liss，Inc.
PURPOSE/OBJECTIVES. The androgen regulated transmembrane serine protease (TMPRSS2) and ETS transcription factor (ERG) gene fusion is a strong prognostic factor for disease recurrence following prostatectomy. Expression of TMPRSS2/ETS-related gene (ERG) fusion gene transcripts is linked with tumor proliferation, invasion, and an aggressive phenotype. The aim of this study was to define the effect of TMPRSS2/ERG fusion gene expression on chemo-and radiosensitivity in prostate tumor cell lines.MATERIALS/METHODS. Clonogenic survival of PC3 and DU145 cells stably expressing TMPRSS2/ERG Types III and VI fusion genes was measured after X-irradiation (0-8 Gy) and Paclitaxel. Cell cycle changes and DNA double-strand break induction and repair were assessed. Differential gene expression was measured by microarray analysis. ERG signaling pathway interactions were studied using Ariadne Pathway Studio.RESULTS. Expression of the TMPRSS2/ERG fusions in PC3 cells increased radiation sensitivity and decreased paclitaxel sensitivity. Increased radiosensitivity was associated with persistent DNA breaks 24 hr post-irradiation, down-regulation of genes involved in DNA repair and mitosis and up-regulation of ETV, an ETS transcription factor. However, DU145 Types III and VI demonstrated a different sensitivity phenotype and gene expression changes. Pathway analysis of ERG signaling further illustrated the variation between the PC3 and DU145 cell lines containing TMPRSS2/ERG fusions.CONCLUSIONS. The effect of TMPRSS2/ERG gene fusions had differing effects on radiosensitivity and chemosensitivity depending on cell line and fusion type. Further work is needed with clinical samples to establish whether TMPRSS2/ERG gene fusions affect radio- and chemosensitivity in vivo. Prostate 71: 1548-1558, 2011. (C) 2011 Wiley-Liss, Inc.