Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

7.3 Tumour Expression Correlation Results
lial cells to possibly regulate apoptosis in the latter [373]. Also in the case of
MT2A we observed an up-regulation in GNS cell lines as well as primary GBM
(Fig 7.4a), but a down-regulation in grade III astrocytoma (Fig 7.4b).
The SULF2 gene encodes a sulfatase that edits the sulfation status of heparan
sulfate proteoglycans on the outside of cells and, in this way, regulates criti-
cal signaling pathways [433]. Disregulation of SULF2 has been implicated in
non-small cell lung cancer [268], pancreatic cancer [357], hepatocellular car-
cinoma [254], breast cancer [344], and gliomas, in which knock-down of the
SULF2 gene resulted in decreased GBM growth in vivo in mice. Molecu-
larly, ablation of SULF2 resulted in decreased PDGFRα phosphorylation and
decreased downstream MAPK signaling activity. Interestingly, of this obser-
vation on the proneural GBM subtype defined by Verhaak et al [511] that is
characterized by aberrations in PDGFRα, showed the strongest SULF2 expres-
sion [391]. In our observations SULF2 was up-regulated in GNS cell lines and
primary GBM (Fig 7.4a), in line with the observations of Phillips et al [391]
that made it a candidate oncogene. We observed SULF2 to also be strongly
up-regulated in grade III astrocytoma (Fig 7.4b) indicating the possibility of a
regulatory impact on behalf of SULF2 early in the progression of the disease.
The DDIT3 gene encodes the pro-apoptotic protein CHOP that is known to
drive the down-regulation of the anti-apoptotic mitochondrial protein Bcl-2,
thereby favouring apoptosis through the activation of cytochrome c and cas-
pase 3. Studies in hepatoma and pheochromocytoma cell lines have shown that
the transcription factor encoded by CEBPB (C/EBPβ) promotes the expres-
sion of DDIT3 [324] and thus of CHOP, which in turn can inhibit C/EBPβ by
dimerizing with it and acting as a dominant negative [324]. This interplay be-
tween CEBPB and DDIT3 may be relevant for glioma therapy development, as
DDIT3 induction in response to a range of compounds sensitises glioma cells to
apoptosis [217]. In line with the pro-apoptotic role of DDIT3 described, we ob-
served up-regulation of the gene in GNS cell lines and primary GBM (Fig 7.4a)
and down-regulation in grade III astrocytoma (Fig 7.4b); similarly, we found
CEBPB to be up-regulated in GNS cell lines and primary GBM (Fig 7.4a),
and down-regulated in grade III astrocytoma (Fig 7.4b). PLS3 (T-plastin)
encodes a regulator of actin organisation and its over-expression in the CV-1
fibroblast-like cell line resulted in partial loss of adherence [27]. The elevated
levels of PLS3 expression we observe in GNS cell lines and primary GBM may
thus be relevant to the invasive phenotype. Accordingly, the less invasive lower
grade III astrocytoma shows down-regulation of PLS3 (Fig 7.4b).
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