Survivin-directed RNA interference cocktail is a potent suppressor of tumour growth in vivo.
BACKGROUND
Survivin is proposed to play a central role in the progression and resistance to therapy of diverse tumour types. High levels of this molecule in tumour cells also correlate with loss of the TP53 tumour suppressor gene, suggesting a molecular connection between TP53 loss and transcriptional induction of Survivin. Patients with TP53 germline mutations, such as those with Li-Fraumeni syndrome, are particularly susceptible to sarcomas, including rhabdomyosarcomas. Our study aimed to identify rhabdomyosarcoma tumours that express Survivin, in order to test novel Survivin-targeted therapies in these tumours.


METHODS
Tumour microarray slides composed of 63 primary rhabdomyosarcoma tumours were stained with a polyclonal antibody to Survivin to identify tumours expressing Survivin. Subcutaneous tumours were then established in NOD/SCID mice using RH30(red) cells, a red fluorescent clone of the RH30 human alveolar rhabdomyosarcoma cell line. Tumours were treated by hydrodynamic injection with a cocktail of Survivin-shRNA-encoding plasmids for a period of 2 weeks.


RESULTS
Over 80% of primary rhabdomyosarcoma tumours expressed Survivin. Treatment of rhabdomyosarcoma xenografts showed greater than 70% reduction in growth when compared with control injected tumours at study completion (average tumour sizes: 1683 v 304 mm3, p<0.05).


CONCLUSIONS
Our findings support a role for Survivin in rhabdomyosarcoma biology and provide preliminary evidence for the therapeutic use of Survivin-targeted RNA interference for human tumours that express high levels of this molecule.
Caldas
H
H
Center for Childhood Cancer, Columbus Children's Research Institute, Columbus, OH 43205, USA.
Holloway
M P
MP
Hall
B M
BM
Qualman
S J
SJ
Altura
R A
RA
D000818:Animals; D002455:Cell Division; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D016513:Mice, SCID; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D012208:Rhabdomyosarcoma / Q000473:pathology*; D000077022:Survivin; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin