Genes associated with 1p-19q LOH.
BMP2 and BMP2R antagonize the proliferative effect of Shh on neural
precursors (1) and negatively affect PI3K/AKT pathway by decreasing PTEN
degradation and increasing PTEN levels (2). Recently it has been shown that human
neural precursor cells could be maintained in vitro in an undifferentiated-like state by
co-stimulation of Wnt and Notch pathways, whereas BMP4 induced an indeterminate
differentiation phenotype characterized by simultaneous expression of glial and
neuronal markers (3). CELSR3 is an atypical cadherin which takes part in planar cell
polarity (PCP) in Drosophila melonogaster; atypical cadherins are not well
characterized in mammals but appear to participate in cell-cell interactions through
adhesion and in regulation of size by controlling proliferation (4), thus suggesting a
negative effect on glioma progression. The amyloid precursor protein (APP) is regulated
by CDK5 (5) and may have an effect on DCX expression (6); it also dimerizes with
Notch2 (7) and thus may have a regulatory role over this pathway. THY1 encodes Thy-1
a membrane-linked protein that activates RhoA to mediate cell-cell contacts and has an
anti-tumorigenic effect (8).
Cyclin G2 (CCNG2) induces p53-dependent cell cycle arrest and its expression
is lowered by PI3K (9). Cyclin G associated kinase (GAK) induces EGFR endocytosis
and therefore can negatively modulate this pathway; GAK down-regulation seems to
promote tumorigenesis (10). E2F5 blocks cell cycle phase S by inhibiting E2F1 (11).
CDK5R1 stimulates CDK5, which in turn activates p53 by stabilization inducing G1
arrest (12).
PKA is thought to promote raft-rich patches clustering; this clustering is required
for microtubule regulated cell motility (13) involving IQGAP1 (which will be discussed
below) and therefore, PKA inhibitors should interfere with this mechanism.
Rho family members are crucial in the regulation of cell migration; it was
recently reported that RhoA promotes stress fiber formation and cell adhesion while Rac
stimulates cell migration (14). MCF2 is a GTP exchange factor that activates RhoA and
thus, its over-expression should activate the RhoA pathway. In fact, RhoA activation was
shown to inhibit motility of glial tumor cells (15). DCX (encoding doublecortin) and
PAFAH1B1 interact with dynein and participate in neuronal migration (16); this might
seem to be contradictory as one would expect genes over-expressed in the 1p-19q LOH
group to be inhibitors of cell migration. Nevertheless, it is possible that over-expression
of genes such as DCX and PAFAH1B1 might affect stoichiometry of scaffold proteins
required for proper migration. Reinforcing our finding, DCX has been postulated as a
glioma tumor suppressor (17).
ACSL6 (Acyl-CoA synthase 2) enhances polyunsaturated fatty acids (PUFAs)
and docosahexaenoic acid (DHA) internalization and therefore affecting cell membrane
composition and architecture. DHA blocks raft formation and inhibits signaling
processes occurring at these specialized membrane regions (18).
Genes associated with 1p-19q ROH.
IQGAP1 has been identified as a marker for poor prognosis in gliomas (19); it is
a scaffold protein promoting cell migration by linking growth factor signaling to
cytoskeleton assembly and therefore can be considered as a crossroad in the
proliferative process ((20) and references therein). In this sense, it has been reported that
IQGAP1 promotes neural progenitor proliferation and VEGF-mediated migration (20),
thus linking migration to angiogenesis. IQGAP1 is an effector of Cdc42 and Rac1,
which play a crucial role in cell motility. IQGAP1 also forms complexes with proteins
encoded by several genes identified in this study such as PLCE1, VCL, WASF2, ITGB2
and ARPC1B, which regulate focal adhesions and motility (20). Vinculin (encoded by
VCL) also interacts with CDK5 (21). PAFAH1B1 (also known as LIS1) is another
IQGAP1 partner. As suggested above, PAFAH1B1 over-expression might affect
IQGAP1 stoichiometry, which is known to be carefully regulated (22); alternatively,
IQGAP1 could also be miss-localized by the excess of LIS1 protein.
SALL1 is a transcriptional repressor that plays a role in chromatin remodeling
and synergistically activates de Wnt pathway (23). This pathway also regulates GLIS3,
which belongs to the GLI family of transcriptional activators and was identified as a
poor outcome marker in ependymomas (24). EMP1 is a gene that activates oncogenesis
and its expression is up regulated by constitutive active mutant EGFR (EGFRvIII) in
glioma cells (25). NOTCH2 is involved in neural and glial progenitor proliferation and
contributes to the stem-like character of glioma cells (26); loss of Notch2 predicts
survival in glial tumors (27). Besides the known function in inflammatory response,
Toll-like receptors (TLR2, TLR5) also control mesenchymal and neural stem cell
proliferation (28).
HMOX1 is an important tool in stress response. It was shown to accumulate in
microglial cells during oligodendroglioma progression and to cooperate in cell survival
(29). MT2A is another gene related to stress response and it was recently found to be up
regulated in astrocytomas (30).
MKNK1 and MKNK2 belong to the MAP kinase family. They are activated by
PI3K to phosphorylate and activate initiation factor 4E (eIF4E); eIF4E is a survival
gene involved in cell cycle progression and resistance to apoptosis (31). Several
mRNAs encoding proteins engaged in oncogenic pathways are regulated at the
translational level; this highlights the importance of MKNK1/2 and eIF4E in cancer
progression (32), adding another level of complexity to this phenomenon.
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