Transcriptional Characterization of Glioma Neural Stem Cells Diva ...

7.3 Tumour Expression Correlation Results
cytoma, but up-regulated in primary GBM (Fig 7.4).
Finally, we found the TAGLN and TES genes to be absent or low in most GNS
lines, but displaying the opposite trend in GBM tissue compared to normal
brain (Fig 7.4c) or grade III astrocytoma (Fig 7.4d). Interestingly, the TES
gene is located on chromosome 7, which is known to be gained in all our GNS
cell lines (see 6.3 section). A strong regulatory effect must be in action in
GNS cell lines to effect the down-regulation of TES. Similarly to the SYNM
gene, TES has been shown to interact with the LIM domain protein Zyxin and
therefore is believed to have a role in cell motility and is often found in focal
adhesions [109]. The TAGLN gene encodes an actin protein found in fibrob-
lasts and smooth muscle, the expression of which is down-regulated in many
cell lines and may be an early marker for the onset of transformation [260].
Both TAGLN and TES have been characterised as tumour suppressors in ma-
lignancies outside the brain and TES is known to often be silenced by promoter
hypermethylation in GBM [30,349].
Altogether, MAF, MYL9, HMGA2, SDC2, SYNM, IRX2, TES and TAGLN
may be part of a GNS expression profile that helps define the stem cell identity
of these cells and the tumour that derives from them according to the cancer
stem cell hypothesis. Interestingly, the expression pattern of most of these
genes is mirrored in grade III astrocytomas.
Of the seven genes that are down-regulated in both GNS cell lines and pri-
mary GBMs, TUSC3 is a candidate tumour suppressor known to be silenced
by promoter methylation in GBM, particularly in patients over 40 years of
age. Loss or down-regulation of TUSC3 has been found in other cancers, such
as colon cancer, where its promoter becomes increasingly methylated with age
in the healthy mucosa [12]. These data suggest that transcriptional changes
in healthy aging tissue, such as TUSC3 silencing, may contribute to the more
severe form of glioma in older patients. In line with its role as tumour suppres-
sor, we found TUSC3 to be down-regulated in GNS cell lines, primary GBM
and grade III astrocytoma (Fig 7.4).
The PLCH1 gene is a member of the phospholipase C family of enzymes that
cleave phosphatidylinositol 4,5-bisphosphate to generate second messengers in-
ositol 1,4,5-trisphosphate and diacylglycerol. PLCH1 is thus involved in phos-
phoinositol signaling [228], just like the frequently mutated phosphoinositide
3-kinase complex [326]. We found PLCH1 to be down-regulated in GNS cell
lines and primary GBM (Fig 7.4c) and slightly up-regulated in grade III as-
trocytoma (Fig 7.4d).
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