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Hypoxic gene regulation and oncogenic pathways in neuroblastoma

Fredlund, Erik LU (2008) In Faculty of Medicine Doctoral Dissertation Series 2008:29.
Abstract
Neuroblastoma patients show remarkable clinical heterogeneity, with courses ranging from spontaneous regression to fatal tumor progression despite intense multi-modal treatment.



Previous studies have shown that hypoxia pushes neuroblastoma cells towards a more immature phenotype, which correlates to aggressive disease. Here we define a role for the hypoxia inducible factor-2α in neuroblastoma tumor progression. While HIF-1α was transiently stabilized at hypoxia (1% oxygen), HIF-2α was induced and regulated HIF-specific target genes, such as VEGF, at later time points. Furthermore, HIF-2α was stabilized and transcriptionally active in cells grown at physiological oxygen levels (5% O2). Subsequent microarray analysis... (More)
Neuroblastoma patients show remarkable clinical heterogeneity, with courses ranging from spontaneous regression to fatal tumor progression despite intense multi-modal treatment.



Previous studies have shown that hypoxia pushes neuroblastoma cells towards a more immature phenotype, which correlates to aggressive disease. Here we define a role for the hypoxia inducible factor-2α in neuroblastoma tumor progression. While HIF-1α was transiently stabilized at hypoxia (1% oxygen), HIF-2α was induced and regulated HIF-specific target genes, such as VEGF, at later time points. Furthermore, HIF-2α was stabilized and transcriptionally active in cells grown at physiological oxygen levels (5% O2). Subsequent microarray analysis showed that HIF-2α induced genes, previously identified as hypoxia regulated, at this physiological oxygen level. Several of these genes have been implicated in tumorigenic processes and correlated to adverse patient outcome in various tumor forms. Indeed, siRNA mediated knock-down of HIF-2α in neuroblastoma cells significantly reduced xenograft tumor growth, as compared to siHIF1-α treated or wild-type cells. Moreover, immunohistochemical analyses of a large neuroblastoma tumor material arranged in a tissue microarray showed that HIF-2α expression correlated to VEGF, and that high HIF-2α levels was predictive of poor patient prognosis.



Prognostic markers of neuroblastoma patient adverse prognosis include amplification of the MYCN oncogene and an undifferentiated morphology. While these features discriminate high- from low-risk patients with precision, identification of poor outcome low- and intermediate-risk patients is more challenging. We analyze two large neuroblastoma microarray data sets by using a priori-defined gene expression signatures. The results show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predict relapse and death from disease. This was evident not only for high-risk patients, but also was robust in identifying groups of poor prognosis patients otherwise judged to be at low- or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma. (Less)
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author
supervisor
opponent
  • Ph.D. Versteeg, Rogier, Department of Genetics, AMC, University of Amsterdam
organization
publishing date
type
Thesis
publication status
published
subject
keywords
microarray, hypoxia, MYCN, gene expression analysis, Neuroblastoma, Myc, pathway analysis, differentiation
in
Faculty of Medicine Doctoral Dissertation Series
volume
2008:29
pages
150 pages
publisher
Lund University Press
defense location
Patologens föreläsningssal, Ing 78, UMAS
defense date
2008-03-28 09:15
ISSN
1652-8220
ISBN
978-91-85897-82-7
language
English
LU publication?
yes
id
a57aae3b-39d1-4ebb-8b39-da5eb9334082 (old id 1045359)
date added to LUP
2008-03-11 12:50:25
date last changed
2016-09-19 08:44:46
@phdthesis{a57aae3b-39d1-4ebb-8b39-da5eb9334082,
  abstract     = {Neuroblastoma patients show remarkable clinical heterogeneity, with courses ranging from spontaneous regression to fatal tumor progression despite intense multi-modal treatment. <br/><br>
<br/><br>
Previous studies have shown that hypoxia pushes neuroblastoma cells towards a more immature phenotype, which correlates to aggressive disease. Here we define a role for the hypoxia inducible factor-2α in neuroblastoma tumor progression. While HIF-1α was transiently stabilized at hypoxia (1% oxygen), HIF-2α was induced and regulated HIF-specific target genes, such as VEGF, at later time points. Furthermore, HIF-2α was stabilized and transcriptionally active in cells grown at physiological oxygen levels (5% O2). Subsequent microarray analysis showed that HIF-2α induced genes, previously identified as hypoxia regulated, at this physiological oxygen level. Several of these genes have been implicated in tumorigenic processes and correlated to adverse patient outcome in various tumor forms. Indeed, siRNA mediated knock-down of HIF-2α in neuroblastoma cells significantly reduced xenograft tumor growth, as compared to siHIF1-α treated or wild-type cells. Moreover, immunohistochemical analyses of a large neuroblastoma tumor material arranged in a tissue microarray showed that HIF-2α expression correlated to VEGF, and that high HIF-2α levels was predictive of poor patient prognosis.<br/><br>
<br/><br>
Prognostic markers of neuroblastoma patient adverse prognosis include amplification of the MYCN oncogene and an undifferentiated morphology. While these features discriminate high- from low-risk patients with precision, identification of poor outcome low- and intermediate-risk patients is more challenging. We analyze two large neuroblastoma microarray data sets by using a priori-defined gene expression signatures. The results show that differential overexpression of Myc transcriptional targets and low expression of genes involved in sympathetic neuronal differentiation predict relapse and death from disease. This was evident not only for high-risk patients, but also was robust in identifying groups of poor prognosis patients otherwise judged to be at low- or intermediate-risk for adverse outcome. These data suggest that pathway-specific gene expression profiling might be useful in the clinic to adjust treatment strategies for children with neuroblastoma.},
  author       = {Fredlund, Erik},
  isbn         = {978-91-85897-82-7},
  issn         = {1652-8220},
  keyword      = {microarray,hypoxia,MYCN,gene expression analysis,Neuroblastoma,Myc,pathway analysis,differentiation},
  language     = {eng},
  pages        = {150},
  publisher    = {Lund University Press},
  school       = {Lund University},
  series       = {Faculty of Medicine Doctoral Dissertation Series},
  title        = {Hypoxic gene regulation and oncogenic pathways in neuroblastoma},
  volume       = {2008:29},
  year         = {2008},
}