Carr Jane, Bell Emma, Pearson Andrew D J, Kees Ursula R, Beris Helen, Lunec John, Tweddle Deborah A
Northern Institute for Cancer Research, University of Newcastle Upon Tyne, United Kingdom.
Cancer Res. 2006 Feb 15;66(4):2138-45. doi: 10.1158/0008-5472.CAN-05-2623.
p53 mutations have been reported in cell lines derived from relapsed neuroblastoma tumors. We hypothesize that functional inactivation of p53 by mutation or other mechanisms is common in relapsed neuroblastoma and can contribute to chemoresistance. Our aim was to determine the frequency of p53 mutations, p14(ARF) methylation, or deletion and MDM2 amplification in 23 neuroblastoma cell lines (6 derived at diagnosis and 17 derived at relapse). One cell line was p53 mutant (BE2c) and two cell lines were deleted for p14(ARF) (LAN-6 and SHEP). Two cell lines were methylated for p14(ARF) (GIMEN and PER-108), one of which had low levels of p14(ARF) mRNA expression which increased following demethylation with 5-aza-2/deoxycytidine treatment (GIMEN), and four cell lines were confirmed to be MDM2-amplified. All these cell lines were derived from neuroblastomas at relapse. Inactivation of the p53 pathway was observed in 9 out of 17 neuroblastoma cell lines (53%) established at relapse and in none of the cell lines established from pretreatment tumors. If these data are confirmed in neuroblastoma tumors, this suggests that p53-independent therapy and reactivation of inactive p53 approaches would be useful in the management of relapsed neuroblastoma.
在复发的神经母细胞瘤肿瘤衍生的细胞系中已报道有p53突变。我们推测，p53通过突变或其他机制发生功能失活在复发的神经母细胞瘤中很常见，并且可能导致化疗耐药。我们的目的是确定23个神经母细胞瘤细胞系（6个在诊断时获得，17个在复发时获得）中p53突变、p14(ARF)甲基化或缺失以及MDM2扩增的频率。一个细胞系是p53突变型（BE2c），两个细胞系缺失p14(ARF)（LAN-6和SHEP）。两个细胞系的p14(ARF)发生甲基化（GIMEN和PER-108），其中一个细胞系p14(ARF) mRNA表达水平较低，在用5-氮杂-2'-脱氧胞苷处理去甲基化后表达增加（GIMEN），并且四个细胞系被证实存在MDM2扩增。所有这些细胞系均来自复发时的神经母细胞瘤。在复发时建立的17个神经母细胞瘤细胞系中有9个（53%）观察到p53通路失活，而在预处理肿瘤建立的细胞系中未观察到。如果这些数据在神经母细胞瘤肿瘤中得到证实，这表明不依赖p53的治疗以及使失活的p53恢复活性的方法在复发神经母细胞瘤的治疗中将是有用的。
