Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.
Mol Cancer. 2010 Oct 15;9:277. doi: 10.1186/1476-4598-9-277.
The chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response.
We provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5. An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis <12 months, low clinical stage, and favorable histology; P < 0.001 for all), overall survival (OS) (P < 0.001) and event-free survival (EFS) (P < 0.001). Multivariate analysis showed that CHD5 prognostic value is independent of other clinical and biologically relevant parameters, and could therefore represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. The prognostic value of CHD5 was confirmed in an independent, blinded set of 32 NB tumors (P < 0.001).Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival.
The neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.
染色质域解旋酶 DNA 结合蛋白 5（CHD5）是一种潜在的肿瘤抑制基因，位于染色体 1p36 上，该区域在高危神经母细胞瘤（NB）中经常缺失。先前的数据表明，CHD5mRNA 存在于正常神经组织和低危 NB 中，然而，CHD5 蛋白的分布尚未得到探索。本研究旨在研究 CHD5 蛋白表达作为 NB 预后的免疫组织化学标志物。为此，分析了正常神经组织和神经母细胞瘤（NTs）中的 CHD5 蛋白表达。在高危肿瘤的亚组中，我们在诱导化疗后重新检查了 CHD5 基因和蛋白的表达，以确定潜在的反映肿瘤反应的变化。
我们提供的证据表明，CHD5 是一种神经元特异性蛋白，在神经胶质细胞中不存在，在神经元类型中表达多样。在 NTs 中，CHD5 免疫反应性仅局限于分化的神经母细胞和神经节样细胞，而未分化的神经母细胞和基质施万细胞中不存在。发现蛋白和 mRNA 水平之间存在相关性，提示 CHD5 的转录调控。对 90 例原发性 NTs 的免疫组织化学分析强调了 CHD5 表达与有利的预后变量（诊断时年龄<12 个月，临床分期低，组织学良好；均 P<0.001）、总生存（OS）（P<0.001）和无事件生存（EFS）（P<0.001）之间存在很强的相关性。多变量分析表明，CHD5 的预后价值独立于其他临床和生物学相关参数，因此可作为 NB 预后的标志物，可通过常规免疫组织化学进行检测。在 32 例 NB 肿瘤的独立、盲法验证集中证实了 CHD5 的预后价值（P<0.001）。在诱导肿瘤细胞分化特征的高危肿瘤中，观察到 CHD5 表达的再激活。值得注意的是，这些 NB 肿瘤表现出良好的临床反应和延长的患者生存。
神经元特异性蛋白 CHD5 可能是 NB 预后的标志物，可通过常规免疫组织化学进行检测。化疗诱导的 CHD5 表达再建立可能是治疗反应的替代标志物。
