Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Int J Cancer. 2010 May 1;126(9):2012-24. doi: 10.1002/ijc.25074.
High polyamine (PA) levels and ornithine decarboxylase (ODC) overexpression are well-known phenomena in many aggressive cancer types. We analyzed the expression of ODC and ODC-activity regulating genes antizymes 1-3 (OAZ1-3) and antizyme inhibitors 1-2 (AZ-IN1-2) in human neuroblastoma (NB) tumors and correlated these with genetic and clinical features of NB. Since ODC is a known target gene of MYCN, the correlation between ODC and MYCN was of special interest. Data were obtained from Affymetrix micro-array analysis of 88 NB tumor samples. In addition, mRNA expression levels of ODC, OAZ2 and MYCN in a MYCN-inducible NB cell line were determined by quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR). ODC mRNA expression in NB tumors was significantly predictive of decreased overall survival probability and correlated with several unfavorable clinical NB characteristics (all p < 0.005). Interestingly, high ODC mRNA expression also showed significant correlation with poor survival prognosis in Kaplan-Meier analyses stratified for patients without MYCN amplification, suggesting an additional role for ODC independent of MYCN. Conversely, high OAZ2 mRNA expression correlated with increased survival and with several favorable clinical NB characteristics (all p < 0.003). In addition, we provide first evidence of a role for MYCN-associated transcription factors MAD2 and MAD7 in ODC regulation. In NB cell cultures, ectopic overexpression of MYCN altered ODC but not OAZ2 mRNA levels. In conclusion, these data suggest that elevated ODC and low OAZ2 mRNA expression levels correlate with several unfavorable genetic and clinical features in NB, offering new insights into PA pathways and PA metabolism-targeting therapy in NB.
高多胺（PA）水平和鸟氨酸脱羧酶（ODC）过表达是许多侵袭性癌症类型的众所周知的现象。我们分析了人类神经母细胞瘤（NB）肿瘤中 ODC 和 ODC 活性调节基因抗酶 1-3（OAZ1-3）和抗酶抑制剂 1-2（AZ-IN1-2）的表达，并将其与 NB 的遗传和临床特征相关联。由于 ODC 是 MYCN 的已知靶基因，因此 ODC 与 MYCN 之间的相关性特别有趣。数据来自 88 个 NB 肿瘤样本的 Affymetrix 微阵列分析。此外，通过定量实时逆转录聚合酶链反应（RT-PCR）测定了 MYCN 诱导的 NB 细胞系中 ODC、OAZ2 和 MYCN 的 mRNA 表达水平。NB 肿瘤中 ODC mRNA 的表达显着预测总体生存率降低，并与几种不良的 NB 临床特征相关（均 p <0.005）。有趣的是，在分层分析没有 MYCN 扩增的患者的 Kaplan-Meier 分析中，高 ODC mRNA 表达也与较差的生存预后显着相关，这表明 ODC 除了 MYCN 之外还有其他作用。相反，高 OAZ2 mRNA 表达与增加的生存率以及几种有利的 NB 临床特征相关（均 p <0.003）。此外，我们首次提供了 MYCN 相关转录因子 MAD2 和 MAD7 在 ODC 调节中的作用的证据。在 NB 细胞培养物中，MYCN 的异位过表达改变了 ODC 但不改变 OAZ2 mRNA 水平。总之，这些数据表明，升高的 ODC 和低的 OAZ2 mRNA 表达水平与 NB 中的几种不利遗传和临床特征相关，为 PA 途径和 NB 中的 PA 代谢靶向治疗提供了新的见解。
