A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embyronal carcinoma
A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embyronal carcinoma
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DOI：
10.1038/sj.onc.1208755
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发表时间：
2005-09-08
期刊：
影响因子：
8
通讯作者：
Spinella, MJ
中科院分区：
文献类型：
--
作者：
Kerley-Hamilton, JS;Pike, AM;Spinella, MJ
睾丸生殖细胞癌仍然是为数不多的实体肿瘤之一，可以通过传统的以顺铂为基础的化疗在晚期治愈。其机制在很大程度上仍不清楚。通过使用基因表达阵列PRO。让我们去吧。顺铂对睾丸生殖细胞来源的人胚胎癌细胞的反应。我们报告了46个基因被顺铂上调，5个基因被顺铂抑制。其中几个基因产物，包括Fas、TRAILR3、PHLDA3、LRDD和IER3，先前被认为参与了凋亡死亡受体途径，而其他包括SESN1、FDXR、PLK3和DDIT4在内的基因产物则是已知的活性氧产生的介导物。大约54%的上调基因被确定或怀疑是p53的下游靶标。针对P53的特异性siRNA可阻止顺铂介导的P53和P53途径基因的激活，并使胚胎癌细胞对顺铂的细胞毒性产生相对耐药。有趣的是，在p53基因敲除细胞中，几乎整个已识别的顺铂靶点对顺铂没有反应或反应减弱，这表明许多是P53的新的直接或间接靶点，包括GPR87、STK17A、INPP5D、FLJ11259和EPS8L2。这些数据表明，P53的强劲转录激活与已知的睾丸生殖细胞肿瘤对化疗的过敏性有关。许多基因产物可能参与了这种疾病独特的治愈能力。
Testicular germ cell cancers remain one of the few solid tumors routinely cured in advanced stages with conventional cisplatin-based chemotherapy. The mechanisms remain largely unknown. Through use of gene-expression array pro. ling we de. ne immediate transcriptional targets in response to cisplatin in testicular germ cell-derived human embryonal carcinoma cells. We report 46 genes upregulated and five genes repressed by cisplatin. Several of these gene products, including FAS, TRAILR3, PHLDA3, LRDD, and IER3 are previously implicated in the apoptotic death receptor pathway, while others including SESN1, FDXR, PLK3, and DDIT4 are known mediators of reactive oxygen species generation. Approximately 54% of the upregulated genes are established or suspected downstream targets of p53. Specific siRNA to p53 prevents cisplatin-mediated activation of p53 and p53 pathway genes and renders embryonal carcinoma cells relatively resistant to cisplatin cytotoxicity. Interestingly, in p53 knockdown cells nearly the entire set of identified cisplatin targets fail to respond or have a diminished response to cisplatin, suggesting that many are new direct or indirect targets of p53 including GPR87, STK17A, INPP5D, FLJ11259, and EPS8L2. The data indicate that robust transcriptional activation of p53 is linked to the known hypersensitivity of testicular germ cell tumors to chemotherapy. Many of the gene products may participate in the unique curability of this disease.