High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status.
OBJECTIVE
Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels.


METHODS
To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry.


RESULTS
We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCF(Skp2) E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCF(Skp2) E3-ligase, in neuroblastoma tumors.


CONCLUSIONS
Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.
Westermann
Frank
F
Department of Tumor Genetics, German Cancer Research Center, Heidelberg, Germany. f.westermann@dkfz.de
Henrich
Kai-Oliver
KO
Wei
Jun S
JS
Lutz
Werner
W
Fischer
Matthias
M
König
Rainer
R
Wiedemeyer
Ruprecht
R
Ehemann
Volker
V
Brors
Benedikt
B
Ernestus
Karen
K
Leuschner
Ivo
I
Benner
Axel
A
Khan
Javed
J
Schwab
Manfred
M
D050687:E2F1 Transcription Factor / Q000235:genetics; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D007150:Immunohistochemistry; D009447:Neuroblastoma / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D012306:Risk; D044786:S-Phase Kinase-Associated Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D050687:E2F1 Transcription Factor; D012333:RNA, Messenger; D044786:S-Phase Kinase-Associated Proteins