Kerley-Hamilton Joanna S, Pike Aimee M, Li Na, DiRenzo James, Spinella Michael J
Department of Pharmacology and Toxicology, Dartmouth Medical School and Norris Cotton Cancer Center, Hanover, NH 03755, USA.
Oncogene. 2005 Sep 8;24(40):6090-100. doi: 10.1038/sj.onc.1208755.
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 profiling we define 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.
睾丸生殖细胞癌仍然是少数几种在晚期阶段通过常规顺铂化疗能够常规治愈的实体瘤之一。其机制在很大程度上仍然未知。通过使用基因表达阵列分析，我们确定了睾丸生殖细胞来源的人胚胎癌细胞对顺铂反应的直接转录靶点。我们报告了46个被顺铂上调的基因和5个被顺铂下调的基因。这些基因产物中的一些，包括FAS、TRAILR3、PHLDA3、LRDD和IER3，先前已被认为与凋亡死亡受体途径有关，而其他一些，包括SESN1、FDXR、PLK3和DDIT4，是已知的活性氧生成介质。大约54%的上调基因是已确定的或疑似的p53下游靶点。针对p53的特异性小干扰RNA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细胞毒性相对耐药。有趣的是，在p53敲低的细胞中，几乎所有已确定的顺铂靶点对顺铂都无反应或反应减弱，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。数据表明，p53的强大转录激活与睾丸生殖细胞肿瘤对化疗已知的超敏感性有关。许多基因产物可能参与了这种疾病独特的可治愈性。
