Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A
Division of Biochemistry, Chiba Cancer Research Center Research Institute, Japan.
Oncogene. 2000 Feb 3;19(5):617-23. doi: 10.1038/sj.onc.1203358.
Survivin (SVV) is a family member of inhibitor of apoptosis proteins (IAPs) and its expression is cell cycle regulated. The gene is mapped to chromosome 17q25, the region of which is frequently gained in advanced stages of neuroblastoma (NBL). However, the role of SVV in NBL is poorly understood. Here we studied the clinical and biological role of SVV in NBL. A 1.9 kb SVV transcript was expressed in all of 9 NBL cell lines at higher levels than those in adult cancer cell lines. In 34 primary NBLs, high levels of SVV expression was significantly associated with age greater than 12 months (two sample t-test: P= 0.0003), advanced stages (P = 0.0136), sporadic tumors (P= 0.0027) and low levels of TrkA expression (P = 0.0030). In NBL cell lines, SVV mRNA expression was dramatically down-regulated in CHP134 and IMR32 cells undergoing apoptosis after treatment with all-trans retinoic acid (RA) or serum deprivation. It was only moderately decreased in cells (SH-SY5Y and CHP901) undergoing RA-induced differentiation. On the other hand, in proliferating NBL cells or RA-treated SK-N-AS line which is refractory to RA, the SVV mRNA remained at steady state levels or rather up-regulated. Furthermore, transfection of SVV into CHP134 cells induced remarkable inhibition of the RA-induced apoptosis. Collectively, our results suggest that high expression of SVV is a strong prognostic indicator for the advanced stage neuroblastomas, and that it could be one of the candidate genes for the 17q gain.
生存素（SVV）是凋亡抑制蛋白（IAPs）家族的成员之一，其表达受细胞周期调控。该基因定位于17号染色体q25区，在神经母细胞瘤（NBL）晚期阶段该区域常出现扩增。然而，SVV在NBL中的作用尚不清楚。在此，我们研究了SVV在NBL中的临床和生物学作用。一个1.9 kb的SVV转录本在所有9种NBL细胞系中均有表达，且表达水平高于成人癌细胞系。在34例原发性NBL中，SVV高表达与年龄大于12个月（双样本t检验：P = 0.0003）、晚期阶段（P = 0.0136）、散发性肿瘤（P = 0.0027）以及TrkA低表达水平（P = 0.0030）显著相关。在NBL细胞系中，经全反式维甲酸（RA）处理或血清剥夺后，CHP134和IMR32细胞发生凋亡，其SVV mRNA表达显著下调。在经RA诱导分化的细胞（SH-SY5Y和CHP901）中，其表达仅适度降低。另一方面，在增殖的NBL细胞或对RA耐药的经RA处理的SK-N-AS细胞系中，SVV mRNA保持稳定水平或反而上调。此外，将SVV转染到CHP134细胞中可显著抑制RA诱导的凋亡。总体而言，我们的结果表明，SVV高表达是晚期神经母细胞瘤的一个强有力的预后指标，并且它可能是17q扩增的候选基因之一。
