High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma.
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.
Islam
A
A
Division of Biochemistry, Chiba Cancer Research Center Research Institute, Japan.
Kageyama
H
H
Takada
N
N
Kawamoto
T
T
Takayasu
H
H
Isogai
E
E
Ohira
M
M
Hashizume
K
K
Kobayashi
H
H
Kaneko
Y
Y
Nakagawara
A
A
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004789:Enzyme Activation; D004790:Enzyme Induction; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009447:Neuroblastoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011379:Prognosis; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D000077022:Survivin; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D000077022:Survivin; D014212:Tretinoin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases