The role of NOTCH2 gene in human malignant glial brain tumours

Sivasankaran, Balasubramanian. The role of NOTCH2 gene in human malignant glial brain tumours. 2008, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_8559

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Background: Glioblastoma multiforme (GBM), astrocytoma (A) and oligodendroglioma (OG)
are the neoplasms of the glial lineage in the Central Nervous System (CNS). Among them, GBM
occurs at the highest frequency and shows the shortest patient median survival time of some 10
months as compared for instance to the survival time of OG of about 10 years. Genetically, OG
differs from GBM by the frequent combination of loss of heterozygosity (LOH) on chromosomes
1p and 19q, which is associated with more favourable prognosis in OG patients. However, the
clinical significance of LOH on 1p in other glioma subtypes remained unknown.
Methods and Results: We identified a subgroup of GBM with LOH on centromeric chromosome
1p together with longer survival. The minimally lost area(s) in both GBM and OG converged at
the NOTCH2 locus on 1p11 and positively correlated with prognosis in GBM as well as in OG
patients. Comparison between gene expression of NOTCH2 and the genetic status at the NOTCH2
locus on chromosome 1p11 supported the hypothesis of a loss of function alteration of NOTCH2
in tumours. However, many GBMs do not display deletions at the NOTCH2 locus on 1p11 and do
express the NOTCH2 gene. Abundant expression of components of canonical NOTCH signaling
in these tumors and a positive correlation between NOTCH2 transcripts with the target gene
HES-1 (P=0.0001) indicated that functional NOTCH signaling in glioma is mainly driven by
NOTCH2. In addition, we defined TNC, the gene for the cell migration factor tenascin-C as a
novel target gene for NOTCH signaling. We further showed that activation of NOTCH signaling
was indeed promoting TNC-dependent glioma cell motility. Thus, together with the ability to
increase proliferation, canonical Notch signaling turned out to be critical for glioma progression.
We also found that non-canonical Notch signaling was associated with the maintenance of
tumorigenic potential of the GBM cells in soft agar culture. In addition, Notch2 had a prosurvival
effect on GBM cells by upregulating anti-apoptotic proteins Bcl-2 and Mcl-1,
independently of the canonical pathway. Finally, defective degradation pathway of Notch
receptors in GBM cells led to slow receptor turnover, thereby providing additional contribution to
the oncogenic function of Notch2.
Conclusion: This study identified aberrant multi-facetted oncogenic behaviours of Notch
proteins, in particular of Notch2, in GBM. This provided a molecular basis for the higher
aggressiveness of Notch2-positive GBM compared to Notch2-negative GBM or OG, and
suggested Notch2 as a sensible target for new therapeutic approaches against GBM.
Advisors:Rüegg, Markus A.
Committee Members:Merlo, Adrian and Chiquet-Ehrismann, Ruth
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Pharmacology/Neurobiology (Rüegg)
UniBasel Contributors:Rüegg, Markus A.
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:8559
Thesis status:Complete
Number of Pages:133
Identification Number:
edoc DOI:
Last Modified:22 Apr 2018 04:30
Deposited On:08 Apr 2009 18:31

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