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.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.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.Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.
%0 Journal Article
%1 Westermann2007
%A Westermann, Frank
%A Henrich, Kai-Oliver
%A Wei, Jun S.
%A Lutz, Werner
%A Fischer, Matthias
%A König, Rainer
%A Wiedemeyer, Ruprecht
%A Ehemann, Volker
%A Brors, Benedikt
%A Ernestus, Karen
%A Leuschner, Ivo
%A Benner, Axel
%A Khan, Javed
%A Schwab, Manfred
%D 2007
%J Clin Cancer Res
%K Analysis; Array E2F1 Expression Factor, Gene Genes, Humans; Immunohistochemistry; Kinase-Associated Messenger, Neuroblastoma, Oligonucleotide Profiling; Proteins, RNA, Risk; S-Phase Sequence Transcription analysis/genetics/physiology analysis; genetics; myc;
%N 16
%P 4695--4703
%R 10.1158/1078-0432.CCR-06-2818
%T High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status.
%U http://dx.doi.org/10.1158/1078-0432.CCR-06-2818
%V 13
%X 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.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.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.Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.
@article{Westermann2007,
__markedentry = {[bbrors:6]},
abstract = {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.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.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.Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Westermann, Frank and Henrich, Kai-Oliver and Wei, Jun S. and Lutz, Werner and Fischer, Matthias and K{\"{o}}nig, Rainer and Wiedemeyer, Ruprecht and Ehemann, Volker and Brors, Benedikt and Ernestus, Karen and Leuschner, Ivo and Benner, Axel and Khan, Javed and Schwab, Manfred},
biburl = {https://www.bibsonomy.org/bibtex/24fcd4cead858b4649f96cab59a1dd7bf/bbrors},
doi = {10.1158/1078-0432.CCR-06-2818},
institution = {Department of Tumor Genetics, German Cancer Research Center, Heidelberg, Germany. f.westermann@dkfz.de},
interhash = {ba504fa4bf8318bb4040bc4062460b65},
intrahash = {4fcd4cead858b4649f96cab59a1dd7bf},
journal = {Clin Cancer Res},
keywords = {Analysis; Array E2F1 Expression Factor, Gene Genes, Humans; Immunohistochemistry; Kinase-Associated Messenger, Neuroblastoma, Oligonucleotide Profiling; Proteins, RNA, Risk; S-Phase Sequence Transcription analysis/genetics/physiology analysis; genetics; myc;},
language = {eng},
medline-pst = {ppublish},
month = Aug,
number = 16,
owner = {bbrors},
pages = {4695--4703},
pii = {1078-0432.CCR-06-2818},
pmid = {17652624},
timestamp = {2015-04-09T12:36:21.000+0200},
title = {High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status.},
url = {http://dx.doi.org/10.1158/1078-0432.CCR-06-2818},
volume = 13,
year = 2007
}