Expression of survivin in neuroblastoma

survivin在神经母细胞瘤中的表达

• 批准号: 13671872
• 负责人: FUKUZAWA Masahiro
• 金额: $ 2.05万
• 依托单位: Nihon University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671872/
• 关键词: surviving; neuroblastoma; apoptosis; Fas; N-myc

Background/Purpose : Apoptotic factors inducing or preventing cell death may intrinsically govern the behavior of some tumors. Survivin is a recently described member of the inhibitor of apoptosis protein (IAP) family, that is expressed in a cell cycle-dependent manner and is found in tumors of unfavorable histology. This study examines the presence of several apoptotic factors, including survivin, in neuroblastoma (NB) tumors. Clues to surviving function in NB are provided by examining its association with behavior and cell dynamics in tumors and cell lines.Methods : Expression of a panel of apoptosis factors were quantified in 15 NB and related tumors before chemotherapy and in 3 NB cell lines (NB7, N810, and NB16). Survivin and other apoptotic factors, as well N-myc amplification in primary tumors was correlated with recurrent disease and outcome. Proliferation rate, apoptosis assays, cell cycle analysis, and drug- or immune-mediated cell death were assessed in cell lines and evalua … More ted in the context of differential survivin and apoptosis gene expression.Results : All 7 tumors that went on to recur expressed survivin, whereas expression was absent in all 8 tumors that went into remission. N-myc was amplified in 4 (57.1%) of the 7 recurrent tumors. Of the 8 tumors that were cured. Fas was expressed in 3 (38%), TRAIL-R1 in 6 (75%) and tumor necrosis factor (TNF)-R1 in 8 (100%), whereas these pro-apoptotic receptors were present in only 1 (14%), 1 (14%), and 4 (57%) of the 7 tumors that went on to recur, respectively. Of the 3 cell lines, NB10 expressed the least survivin, displayed the lowest proliferation index, and had the fewest number of cells in the G2/M (mitotic) phase of the cell cycle. Furthermore, NB10 also was most sensitive to TNF-related apoptosis-inducing ligand (TRAIL) or etoposide-induced cell death.Conclusions : In primary NB tumors, survivin expression was associated with tumors of high risk and unfavorable prognosis, whereas pro-apoptotic receptor expression was more abundant in tumors of favorable prognosis. In this small series, survivin expression appeared to be more predictive of recurrent disease than N-myc amplification. In cell lines, survivin expression was cell cycle dependent, and its expression was associated with greater resistance to drug- or immune-mediated cell death. Survivin expression may become a useful prognostic marker in NB and could be a potential target for the treatment of this tumor. Less

背景/目的：诱导或阻止细胞死亡的凋亡因子可能在本质上控制着某些肿瘤的行为。Survivin是最近发现的凋亡抑制蛋白（IAP）家族的成员，以细胞周期依赖的方式表达，并在组织学不良的肿瘤中发现。本研究探讨了神经母细胞瘤（NB）肿瘤中几种凋亡因子的存在，包括survivin。通过检查其与肿瘤和细胞系中的行为和细胞动力学的关联，提供了NB存活功能的线索。方法：测定15例NB及相关肿瘤化疗前及3株NB细胞系（NB7、N810、NB16）中凋亡因子的表达。原发性肿瘤中Survivin和其他凋亡因子以及N-myc扩增与复发性疾病和预后相关。在细胞系中评估增殖率、凋亡测定、细胞周期分析和药物或免疫介导的细胞死亡，并在差异生存和凋亡基因表达的背景下进行评估。结果：7例复发肿瘤均表达survivin，而8例缓解期肿瘤均无表达。7例复发肿瘤中有4例（57.1%）出现N-myc扩增。在治愈的8个肿瘤中。Fas在3例（38%）中表达，TRAIL-R1在6例（75%）中表达，肿瘤坏死因子(TNF)-R1在8例（100%）中表达，而这些促凋亡受体分别在7例复发的肿瘤中仅1例（14%）、1例（14%）和4例（57%）中表达。在3个细胞系中，NB10表达的survivin最少，增殖指数最低，处于细胞周期G2/M（有丝分裂）期的细胞数量最少。此外，NB10还对tnf相关的凋亡诱导配体（TRAIL）或依托泊苷诱导的细胞死亡最敏感。结论：在原发性NB肿瘤中，survivin的表达与高危、预后不良的肿瘤相关，而促凋亡受体在预后良好的肿瘤中表达更为丰富。在这个小系列中，survivin表达似乎比N-myc扩增更能预测复发性疾病。在细胞系中，survivin的表达依赖于细胞周期，其表达与对药物或免疫介导的细胞死亡的更大抗性有关。Survivin的表达可能成为NB的一个有用的预后标志物，并可能成为治疗这种肿瘤的潜在靶点。少

项目成果

Azuhata T, Scott D, Takamizawa S, Fukuzawa M, Sandler A: "The Inhibitor of Apoptosis Protein Survivin is Associated with High-Risk Behavior of Neuroblastoma"Journal of Pediatric Surgery. 36・12. 1785-1791 (2001)

Azuhata T、Scott D、Takamizawa S、Fukuzawa M、Sandler A：“凋亡蛋白生存素抑制剂与神经母细胞瘤的高风险行为有关”《小儿外科杂志》36・12（2001 年）。

Fukuzawa M, Sugiura H, Koshinaga T, Ikeda T, Hagiwara N: "Expression of vascular endothelial growth factor and its receptor flk-1 in human neuroblastoma using in situ hybridization"Journal of Pediatric Surgery. 37・12. 1747-1750 (2002)

Fukuzawa M、Sugiura H、Koshinaga T、Ikeda T、Hagiwara N：“利用原位杂交技术在人神经母细胞瘤中表达血管内皮生长因子及其受体 flk-1”，小儿外科杂志 37・12。 ）

Azuhata T, Scott D, Takamizawa S, Wen J, Davidoff A, Fukuzawa M, Sandler A: "The inhibitor of apoptpsis protein survivin is associated with high-risk behavior of neuroblastoma"J Pediatr Surg.. 36(12). 1785-1791 (2001)

Azuhata T、Scott D、Takamizawa S、Wen J、Davidoff A、Fukuzawa M、Sandler A：“凋亡蛋白生存素抑制剂与神经母细胞瘤的高危行为相关”J Pediatr Surg. 36(12)。

Fukuzawa M, Sugiura H, Koshinaga T, Ikeda T, Hagiwara N, Sawada T: "Expression of vascular growth factor and its receptor F1k-1 in human neuroblastoma"J Pediatr Surg.. 37 (12). 1747-1750 (2002)

Fukuzawa M、Sugiura H、Koshinaga T、Ikeda T、Hagiwara N、Sawada T：“人神经母细胞瘤中血管生长因子及其受体 F1k-1 的表达”J Pediatr Surg. 37 (12)。

Azuhata T, Scott D, Takamizawa S, Fukuzawa M, Sandler A: "The Inhibitor of Apoptosis Protein Survivn Is Associated with High-Risk Behavior of Neuroblastoma"Journal of Pediatric Surgery. 36・12. 1785-1791 (2001)

Azuhata T、Scott D、Takamizawa S、Fukuzawa M、Sandler A：“凋亡蛋白存活的抑制剂与神经母细胞瘤的高风险行为有关”《小儿外科杂志》36・12（2001）。