Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Meibergdreef 15, PO Box 22700, 1105 AZ Amsterdam, The Netherlands.
Endocr Relat Cancer. 2011 Oct 27;18(6):657-68. doi: 10.1530/ERC-11-0207. Print 2011 Oct.
BIRC5 (survivin) is one of the genes located on chromosome arm 17q in the region that is often gained in neuroblastoma. BIRC5 is a protein in the intrinsic apoptotic pathway that interacts with XIAP and DIABLO leading to caspase-3 and caspase-9 inactivation. BIRC5 is also involved in stabilizing the microtubule-kinetochore dynamics. Based on the Affymetrix mRNA expression data, we here show that BIRC5 expression is strongly upregulated in neuroblastoma compared with normal tissues, adult malignancies, and non-malignant fetal adrenal neuroblasts. The over-expression of BIRC5 correlates with an unfavorable prognosis independent of the presence of 17q gain. Silencing of BIRC5 in neuroblastoma cell lines by various antisense molecules resulted in massive apoptosis as measured by PARP cleavage and FACS analysis. As both the intrinsic apoptotic pathway and the chromosomal passenger complex can be therapeutically targeted, we investigated in which of them BIRC5 exerted its essential anti-apoptotic role. Immunofluorescence analysis of neuroblastoma cells after BIRC5 silencing showed formation of multinucleated cells indicating mitotic catastrophe, which leads to apoptosis via P53 and CASP2. We show that BIRC5 silencing indeed resulted in activation of P53 and we could rescue apoptosis by CASP2 inhibition. We conclude that BIRC5 stabilizes the microtubules in the chromosomal passenger complex in neuroblastoma and that the apoptotic response results from mitotic catastrophe, which makes BIRC5 an interesting target for therapy.
BIRC5（survivin）是位于染色体 17q 臂上的基因之一，在神经母细胞瘤中经常扩增。BIRC5 是内在凋亡途径中的一种蛋白质，与 XIAP 和 DIABLO 相互作用，导致 caspase-3 和 caspase-9 失活。BIRC5 还参与稳定微管-动粒动力学。基于 Affymetrix mRNA 表达数据，我们在此表明，与正常组织、成人恶性肿瘤和非恶性胎儿肾上腺神经母细胞瘤相比，BIRC5 在神经母细胞瘤中的表达明显上调。BIRC5 的过度表达与预后不良相关，与 17q 扩增的存在无关。通过各种反义分子沉默神经母细胞瘤细胞系中的 BIRC5，会导致 PARP 切割和 FACS 分析检测到的大量细胞凋亡。由于内在凋亡途径和染色体乘客复合物都可以作为治疗靶点，我们研究了 BIRC5 在其中哪个途径中发挥其重要的抗凋亡作用。沉默 BIRC5 后神经母细胞瘤细胞的免疫荧光分析显示形成多核细胞，表明有丝分裂灾难，这会通过 P53 和 CASP2 导致细胞凋亡。我们表明，沉默 BIRC5 确实导致了 P53 的激活，并且我们可以通过 CASP2 抑制来挽救凋亡。我们得出结论，BIRC5 稳定了神经母细胞瘤中染色体乘客复合物中的微管，凋亡反应源于有丝分裂灾难，这使得 BIRC5 成为一个有趣的治疗靶点。
