Expression of genes belonging to the IGF-system in glial tumors
The discrepancies arising from conflicting evidence on the results obtained by different laboratories in human gliomas are discussed. Our data highlight the importance of viewing the IGF-related proteins as a complex multifactorial system and show that changes in the expression levels of any one com...
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| Zitieren: | Expression of genes belonging to the IGF-system in glial tumors / V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko, V.I. Rymar, A.A. Stepanenko, O.V. Balynska, T.A. Malisheva, V.D. Rozumenko, Y.P. Zozulya // Цитология и генетика. — 2011. — Т. 45, № 4. — С. 41-57. — Бібліогр.: 69 назв. — англ. |
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Dmitrenko, V.V. Kavsan, V.M. Boyko, O.I. Rymar, V.I. Stepanenko, A.A. Balynska, O.V. Malisheva, T.A. Rozumenko, V.D. Zozulya, Y.P. 2014-07-23T18:47:32Z 2014-07-23T18:47:32Z 2011 Expression of genes belonging to the IGF-system in glial tumors / V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko, V.I. Rymar, A.A. Stepanenko, O.V. Balynska, T.A. Malisheva, V.D. Rozumenko, Y.P. Zozulya // Цитология и генетика. — 2011. — Т. 45, № 4. — С. 41-57. — Бібліогр.: 69 назв. — англ. 0564-3783 https://nasplib.isofts.kiev.ua/handle/123456789/66864 577.21:577.214.622 + 616–006.484.04 The discrepancies arising from conflicting evidence on the results obtained by different laboratories in human gliomas are discussed. Our data highlight the importance of viewing the IGF-related proteins as a complex multifactorial system and show that changes in the expression levels of any one component of the system, in a given malignancy, should be interpreted with caution. As IGF targeting for anticancer therapy is rapidly becoming clinical reality, an understanding of this complexity is very timely. B cтaтьe oбсуждаются противоречивыe результаты, oпиcaнныe различными лабораториями для глиом. Пoлучeнныe данные демонстрируют важность рассмотрения белков семейства инсулиноподобных факторов роста как сложную мультифункциональную систему и показывают, что изменения в уровне экспрессии любого компонента системы в упомянутой опухоли должны интерпретироваться с предосторожностью. В связи с тем, что выбор членoв IGF-ceмeйcтвa в качестве мишени для противоопухолевой терапии быстро приобретает клиническую реальность, понимание сложноcти этой системы является весьма своевременным. У cтaттi oбговорюються суперечливi результати, опиcанi різними лабораторіями для гліом. Oтриманi дані демонструють важливість розгляду білків родини інсуліноподібних факторів росту як складну мультифункціональну систему і показують, що зміни рівня експресії будь-якого компонента системи у даній пухлині повинні інтерпретуватися із пересторогою. В зв’язку з тим, що вибір членiв IGF-ciмeйcтвa як мішені для протипухлинної терапії швидко набуває клінічної реальності, розуміння цієї системи є вельми своєчасним. en Інститут клітинної біології та генетичної інженерії НАН України Цитология и генетика Оригинальные работы Expression of genes belonging to the IGF-system in glial tumors Экспрессия генов, относящихся к IGF-системе, в глиальных опухолях Експресія генів, що належать до IGF-системи, у гліальних пухлинах Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| collection |
DSpace DC |
| title |
Expression of genes belonging to the IGF-system in glial tumors |
| spellingShingle |
Expression of genes belonging to the IGF-system in glial tumors Dmitrenko, V.V. Kavsan, V.M. Boyko, O.I. Rymar, V.I. Stepanenko, A.A. Balynska, O.V. Malisheva, T.A. Rozumenko, V.D. Zozulya, Y.P. Оригинальные работы |
| title_short |
Expression of genes belonging to the IGF-system in glial tumors |
| title_full |
Expression of genes belonging to the IGF-system in glial tumors |
| title_fullStr |
Expression of genes belonging to the IGF-system in glial tumors |
| title_full_unstemmed |
Expression of genes belonging to the IGF-system in glial tumors |
| title_sort |
expression of genes belonging to the igf-system in glial tumors |
| author |
Dmitrenko, V.V. Kavsan, V.M. Boyko, O.I. Rymar, V.I. Stepanenko, A.A. Balynska, O.V. Malisheva, T.A. Rozumenko, V.D. Zozulya, Y.P. |
| author_facet |
Dmitrenko, V.V. Kavsan, V.M. Boyko, O.I. Rymar, V.I. Stepanenko, A.A. Balynska, O.V. Malisheva, T.A. Rozumenko, V.D. Zozulya, Y.P. |
| topic |
Оригинальные работы |
| topic_facet |
Оригинальные работы |
| publishDate |
2011 |
| language |
English |
| container_title |
Цитология и генетика |
| publisher |
Інститут клітинної біології та генетичної інженерії НАН України |
| format |
Article |
| title_alt |
Экспрессия генов, относящихся к IGF-системе, в глиальных опухолях Експресія генів, що належать до IGF-системи, у гліальних пухлинах |
| description |
The discrepancies arising from conflicting evidence on the results obtained by different laboratories in human gliomas are discussed. Our data highlight the importance of viewing the IGF-related proteins as a complex multifactorial system and show that changes in the expression levels of any one component of the system, in a given malignancy, should be interpreted with caution. As IGF targeting for anticancer therapy is rapidly becoming clinical reality, an understanding of this complexity is very timely.
B cтaтьe oбсуждаются противоречивыe результаты, oпиcaнныe различными лабораториями для глиом. Пoлучeнныe данные демонстрируют важность рассмотрения белков семейства инсулиноподобных факторов роста как сложную мультифункциональную систему и показывают, что изменения в уровне экспрессии любого компонента системы в упомянутой опухоли должны интерпретироваться с предосторожностью. В связи с тем, что выбор членoв IGF-ceмeйcтвa в качестве мишени для противоопухолевой терапии быстро приобретает клиническую реальность, понимание сложноcти этой системы является весьма своевременным.
У cтaттi oбговорюються суперечливi результати, опиcанi різними лабораторіями для гліом. Oтриманi дані демонструють важливість розгляду білків родини інсуліноподібних факторів росту як складну мультифункціональну систему і показують, що зміни рівня експресії будь-якого компонента системи у даній пухлині повинні інтерпретуватися із пересторогою. В зв’язку з тим, що вибір членiв IGF-ciмeйcтвa як мішені для протипухлинної терапії швидко набуває клінічної реальності, розуміння цієї системи є вельми своєчасним.
|
| issn |
0564-3783 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/66864 |
| citation_txt |
Expression of genes belonging to the IGF-system in glial tumors / V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko, V.I. Rymar, A.A. Stepanenko, O.V. Balynska, T.A. Malisheva, V.D. Rozumenko, Y.P. Zozulya // Цитология и генетика. — 2011. — Т. 45, № 4. — С. 41-57. — Бібліогр.: 69 назв. — англ. |
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УДК 577.21:577.214.622 + 616–006.484.04
V.V. DMITRENKO 1, V.M. KAVSAN 1, O.I. BOYKO 1,
V.I. RYMAR 1, A.A. STEPANENKO 1, O.V. BALYNSKA 1,
T.A. MALISHEVA 2, V.D. ROZUMENKO 2, Y.P. ZOZULYA 2
1
Institute of Molecular Biology and Genetics, Kyiv, Ukraine
2
A.P. Romodanov Institute of Neurosurgery, Kyiv, Ukraine
E�mail: dmitrenko@imbg.org.ua
EXPRESSION OF GENES
BELONGING TO THE IGF�SYSTEM
IN GLIAL TUMORS
Increased expression of the insulin�like growth factor
(IGF) family members, IGF1, IGF2, their receptors and bind�
ing proteins, or combinations thereof has been documented in
various malignancies including gliomas. The results of multi�
ple investigations suggest that the IGFs can play a paracrine
and/or autocrine role in promoting tumor growth in situ dur�
ing tumor progression but that these roles may vary depending
on the tissue of origin. Enhanced IGF1 expression was not
found in glioblastomas and it was supposed that IGF1 partic�
ipation in the development of glial tumors may be substituted
by protein products of highly expressed other genes, also par�
ticipating in PI3K and MAPK pathways. Increased expression
of IGF�binding protein genes in brain tumors makes the pic�
ture even more complicated. As other binding proteins,
IGFBPs regulate the activity of their ligands by prolonging
their half�life. The discrepancies arising from conflicting evi�
dence on the results obtained by different laboratories in
human gliomas are discussed. Our data highlight the impor�
tance of viewing the IGF�related proteins as a complex multi�
factorial system and show that changes in the expression levels
of any one component of the system, in a given malignancy,
should be interpreted with caution. As IGF targeting for anti�
cancer therapy is rapidly becoming clinical reality, an under�
standing of this complexity is very timely.
Introduction. In recent years, evidences have
been appearing that the members of IGF system
may be involved in cancer development. The anti�
sense strategies, directed to the components of
IGF�signaling, are the subject of many clinical tri�
als. All three IGF receptors (IGF1R, INSR and
IGF2R) are very well known targets for anti�can�
cer therapy. Increased expression of IGF1 recep�
tor same as its ligands may stimulate PI3K and
MAPK signaling cascades leading to cell prolifer�
ation [1–3].
However, the role of IGFs, IGF receptors and
IGF�binding proteins (IGFBPs) in tumor develop�
ment is poorly understood to this time. Increased
levels of IGF1, IGF2 and their receptors have
been found in different tumor types (reviewed in
[4]), although the data about IGF1 and IGF2 gene
expression in astrocytic gliomas are quite ambiguous.
There are several publications reporting enhanced
expression of these genes in anaplastic astrocytomas
and glioblastomas on the RNA or protein levels
[5–8]. For example, Sandberg et al. [5] analysed
the expression of IGF genes by slot blot and
Northern blot hybridization and found several fold
increased IGF1 and IGF2 mRNA levels in one
anaplastic astrocytoma and three glioblastoma
specimens analyzed as compared to different
regions of human adult normal brain. In other
work, these authors demonstrated by immunohis�
tochemistry the production of IGF1�like peptide
in tumor cells in two of three anaplastic astrocy�
tomas and in three of four glioblastomas examined
[6]. In situ hybridization and immunocytochem�
istry also have localized a production of both
IGF1 and IGF2 mRNA and protein in small num�
ber of astrocytoma samples analyzed that was
accompanied by the co�expression of respective
type�1 and type�2 IGF receptors [7]. Immunocyto�
chemical analysis of 39 astrocytic tumors of WHO
grades II–IV revealed tumor cells expressing
IGF1 and IGF1R in all tumor grades (however,
authors do not show how many of samples being
under investigation were positive) [8].
On the other hand, the expression of IGF1 and
IGF2 genes in astrocytic tumors was not found in
other investigations. Thus, IGF2 mRNA was not
detected by Northern analysis in 5 astrocytomas
and 2 glioblastomas [9], and the expression of IGF1
was not found by Northern analysis in two investi�
gated gliomas (ependymoma and glioblastoma)
[10]. Earlier, we also could not find the significant
change of IGF1 gene expression in glioblastoma by
ІSSN 0564–3783. Цитология и генетика. 2011. № 5 41
© V.V. DMITRENKO, V.M. KAVSAN, O.I. BOYKO, V.I. RYMAR,
A.A. STEPANENKO, O.V. BALYNSKA, T.A. MALISHEVA,
V.D. ROZUMENKO, Y.P. ZOZULYA, 2011
Serial Analysis of Gene Expression (SAGE) [11].
Such contradictory results could be explained by
not enough big quantity of samples being under
investigations. Nevertheless, IGF1 and IGF2 genes
were not presented also in the lists of the genes
with significant expression changes in the articles
on integrative genome�wide analysis of 81 [12] and
460 glioblastoma samples [13].
Expression of insulin�like growth factor bind�
ing protein (IGFBP) genes in brain tumors makes
the picture even more complicated. The IGFBP
family consists of six high�affinity members
(IGFBP1–IGFBP6) and four low�affinity pro�
teins (IGFBP7–IGFBP10) which contain on the
NH2�termini conserved «IGFBP motif» (GCGC�
CXXC), share significant structural homology with
IGFBP1–IGFBP6, and able specifically bind
IGFs, although with relatively low affinity [14]. As
other binding proteins, IGFBPs regulate the activ�
ity of their ligands by prolonging their half�life.
The biological actions of IGFs may be regulated by
IGFBPs either negatively or positively, depending
on the tissue type and the physiological or patho�
logical status, some of the IGFBPs also act by a
mechanism independent of IGFs. Elevation of the
activity of IGF1 and IGF2 in the absence of the
increasing of their genes expression may be a result
of the enhancement of stability and lifetime due to
the interaction with IGFBPs [15]. In addition to
functioning in extracellular fluids as simple carrier
proteins regulating circulating IGF turnover,
transport, and distribution, the locally produced
IGFBPs act as autocrine/paracrine regulators of
IGF action [16].
Here, we analyze the expression of IGF system
members including all ten IGFBP genes in
glioblastoma by different methods to clarify their
expression patterns in this tumor.
Materials and methods. SAGE Genie database
(http://cgap.nci.nih.gov/SAGE) was used for the
comparison of gene expression in glioblastoma and
human normal brain by Digital Gene Expression
Displayer (DGED) tool. Two pools of SAGE�
libraries (9 libraries of glioblastoma and 5 normal
adult human brain libraries) were compared. Data,
obtained by microarray analysis and available in
Gene Expression Omnibus (GEO) site (http://
www.ncbi.nlm. nih.gov/geo), were used also for
the comparison of these genes expression in glial
tumors and normal brain. DataSet files were
searched by keywords «glioblastoma», «astrocy�
toma», and «normal brain». A DataSet represents
a collection of biologically� and statistically�com�
parable samples processed using the same plat�
form. In order to measure expression levels from
different DataSet files accurately, normalization
by several housekeeping genes was required.
Scripts, written in Perl were used for the analysis of
these data.
Glioblastoma surgical specimens were classi�
fied on the basis of examination of hematoxylin
and eosin stained sections according to World
Health Organization (WHO) criteria [17]. Surgical
specimens of histologically normal brain tissue
adjacent to tumors were used as a source of normal
adult human brain RNA and protein. All patients
were being treated at the hospital of A.P. Romodanov
Institute of Neurosurgery (Kyiv, Ukraine). The
study protocol was approved by the human ethics
review committees of both institutionsand a signed
consent forms from patients were obtained. The
tissue samples were stored at –70 °С until analysis.
RNA was extracted from frozen samples as described
in our previous articles [11, 18].
Equal amounts of total cellular RNA (5 μg each
for 20 μl mixture) were transcribed into cDNA
with an oligo (dT)/random hexamer primers and
Revert Aid M�MuLV reverse transcriptase («Fer�
mentas», Lithuania). Each semi�quantitative RT�
PCR was performed in 25 μl reaction mixture con�
taining cDNA synthesized on 50 ng of RNA (2 μl
of 10�fold diluted cDNA), 2U Dream Taq Green
DNA polymerase ((«Fermentas», Lithuania), man�
ufacturer’s buffer, 0.2 mM dNTPs, and 10 μM
gene�specific primers (Table 1). Thermal cycling
parameters were: initial denaturing step at 95 °С
for 2 min, followed by 27–35 cycles of denatura�
tion at 95 °С for 30 sec, annealing at 56 0C for
30 sec, synthesis at 72 °С for 30 sec, and final
extension incubation at 72 °С for 7 min. The
number of cycles was chosen so that the PCR
product amplification rate was in the linear phase.
Amplified products were electrophoresed in a
1.5 % agarose gel. Densitometric analysis of PCR
product bands was carried out by using the Scion
Image 1.62c program. Relative expression levels of
examined genes were estimated by normalization
to the expression level of control gene, β�actin
(ACTB). Data obtained with ACTB were used for
calculation of P�value of gene expression changes
ISSN 0564–3783. Цитология и генетика. 2011. № 542
V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko et al.
in glioblastoma by unpaired t�test assuming
unequal variance.
Real�time PCR was performed with the iCycler
iQ5 (BIO�RAD, USA). Reaction mixture (20 μl)
contained 2 μl cDNA (quantity equivalent to syn�
thesized on 50 ng of total RNA), 10 μl MaximaTM
SYBR Green qPCR Master Mix («Fermentas»)
and 10 pmole of each IGF1, IGF2 and IGF1R
gene�specific primer (Table 1). The amplification
procedure of target genes was as follows: initial
denaturing step at 95 °С for 10 min, followed by
40 cycles of denaturation at 95 °С for 15 sec,
annealing at 56 °С for 15 sec and extension at
72 °С for 15 sec. Melting curve analysis was per�
formed to confirm amplification of single bands.
Reaction efficiency was calculated by R package
named qpcR package [19]. Gene expression values
(relative mRNA levels) were calculated based on
the modified ��Cq method [20] as ratio of effi�
ciency raised to power Ct of analyzed gene to effi�
ciency increased to power Ct of reference gene
(ACTB).
Results. Serial Analysis of Gene Expression
(SAGE) revealed a very low level of IGF1 gene
expression in glioblastoma. Thus, tag TTTGAT�
TAAT corresponding to three known long IGF1
transcripts (7370 bases variant 1 mRNA, Ac.No
NM_001111283; 7204 bases variant 2 mRNA,
Ac.No NM_001111284, and 7321 bases variant
4 mRNA, Ac.No NM_000618) was found as only
one tag per 101053 tags in one (SAGE_Brain_
glioblastoma_B_R20) of nine adult glioblastoma
ІSSN 0564–3783. Цитология и генетика. 2011. № 5 43
Expression of genes belonging to the IGF�system in glial tumors
Table 1
Primers used in this work for the analysis of gene expression
Gene name Cycle numberPrimer sequences PCR product size
IGF�I
IGF�II
IGF�IR
IGFBP1
IGFBP2
IGFBP3
IGFBP4
IGFBP5
IGFBP6
IGFBP7
IGFBP8
IGFBP9
IGFBP10
ACTB
32
35
32
32
32
29
29
29
32
29
25
32
29
27
242
249
247
271
224
226
284
130
353
366
259
273
231
262
For GTCCTCCTCGCATCTCTTC
Rev ACATCTCCAGCCTCCTTAG
For ACACCCTCCAGTTCGTCT
Rev ACTGCTTCCAGGTGTCATA T
For ACAGAGAACCCCAAGACTGAGG
Rev TGATGTTGTAGGTGTCTGCGGC
For CGGAGATAACTGAGGAGGA
Rev CACTGTCTGCTG TGATAAAATC
For CTCAAGTCGGGTATGAAGG
Rev GAGTAGAGGTGCTCCAGA
For GCACAGATACCCAGAACT
Rev CCATACTTATCCAC A CACCA
For ACCTCTACATCATCCCCAT
Rev TCAGACTCAGACTCCAC T
For GACCGCAAAGGATTCTACAA
Rev ACTGAAAGTCCCCGTCAA
For GCAACTCCAGACTGAGGTC
Rev CTCGGTTTTTTGTTGAGTGATG
For CCATGACTACTTTTAACCATGCAG
Rev GGTGTACTTGAGCTGTGAGGTC
For GGCTTACCGACTGGAAGAC
Rev GATAGGCTTGGAGATTTTGGG
For CTGTGGTATGGGGTTCTC
Rev TGGATGGTTTTGGTATTGTG
For GCTCCCTGTTTTTGGAATG
Rev CATTTCTTGCCCTTTTTCAG
For AACTACCTTCACATCCATCA
Rev GTACATACTCCTGCTTGCT
SAGE�libraries from Cancer Genome Anatomy
Project database. No one glioblastoma SAGE�
library contains the tag CCCAAGACCC corre�
sponding to the shortest IGF1 transcript (949 bases
variant 3 mRNA, Ac No NM_001111285).
Gene Expression Omnibus (GEO) Datasets
(http://www.ncbi.nlm.nih.gov/gds) were used to
increase the statistical significance of SAGE results.
Obtained files represented the experimental data on
gene expression according to microarray analysis.
Altogether, there were found six DataSet files which
contained data concerning gene expression in
225 glioblastoma and 71 normal brain samples
(Table 2). To compare data from experiments with
different microarray platforms, we used a normal�
ization method proposed for real�time PCR by
dividing expression level of every gene on geometric
average of three housekeeping genes, ACTB, glycer�
aldehyde 3�phosphate dehydrogenase (GAPDH)
and TATA�box binding protein (TBP) [27].
In GEO repository, IGF1 gene set consists of
three different probes corresponded to three
nucleotide sequences in GeneBank (AU144912,
M29644 and M37484) and represented different
ISSN 0564–3783. Цитология и генетика. 2011. № 544
V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko et al.
Table 2
Characteristics of DataSet files from Gene Expression Omnibus (GEO) repository used for the evaluation
of gene expession changes in glioblastoma
GDS1975
GDS1815
GDS1096
GDS1962
GDS3069
GDS596
GPL96
[HG�U133A]
Affymetrix Human
Genome U133A Array
GPL96
[HG�U133A]
Affymetrix Human
Genome U133A Array
GPL96
[HG�U133A]
Affymetrix Human
Genome U133A Array
GPL570
[HG�U133_ Plus_2]
Affymetrix Human
Genome U133 Plus 2.0
Array
GPL96
[HG�U133A]
Affymetrix Human
Genome U133A Array
GPL96
[HG�U133A]
Affymetrix Human
Genome U133A Array
Freije et al., 2004
[21]
Phillips et al.,
2006
[22]
Ge et al., 2005
[23]
Sun et al., 2006
[24]
Liu et al., 2007
[25]
Su et al., 2004
[26]
Large�scale gene expression analysis using the Affymetrix HG
U133 oligonucleotide arrays on 85 diffuse infiltrating gliomas of
all histologic types to assess whether a gene expression�based,
histology�independent classifier is predictive of survival and to
determine whether gene expression signatures provide insight
into the biology of gliomas
77 primary high�grade astrocytomas and 23 matched recur�
rences were profiled to identify changes in gene expression that
relate to both survival and disease progression. Samples include
WHO grade III and IV astrocytomas with a wide range of sur�
vival times. Novel prognostic subclasses of high�grade astrocy�
toma are identified and discovered to resemble stages in neuro�
genesis
Genome�wide expression profiling of 36 types of normal human
tissues. Each RNA tissue sample pooled from several donors.
2503 tissue�specific genes were identified. Results provide base�
lines for interpretation of gene expression profiles of cancers.
mRNA expression data were collected from patients with brain
tumor to improve diagnostic of gliomas on molecular level. 23
samples from epilepsy patients were used as non�tumor samples.
157 tumor samples included 26 astrocytomas, 50 oligoden�
drogliomas and 81 glioblastomas
Analysis of 12 primary brain tumor biopsies with some variation
in their histological diagnoses. These results, together with those
obtained from miRNA profiling by real�time PCR, provide
insight into the relationship between endogenous fluctuations in
miRNA and mRNA expression levels
Designed custom arrays that interrogate the expression of the
vast majority of protein�encoding human and mouse genes were
used to profile a panel of 79 human and 61 mouse tissues. The
resulting data set provides the expression patterns for thousands
of predicted genes, as well as known and poorly characterized
genes, from mice and humans
File name Microarray platform Authors/Reference Short description of the experiments
regions of IGF1 mRNA. Although the results were
little bit different for each probe (Fig. 1), the aver�
age IGF1 gene expression level was even 1,5�fold
lower in glioblastoma than in anaplastic astrocy�
toma or human normal brain with P < 0.05 (the
significance of differences was calculated using
unpaired two�tailed t�test and assuming unequal
variance (Table 3). Analysis of each DataSet file
for each IGF1 probe also did not reveal significant
differences in IGF1 expression between glioblas�
toma, anaplastic astrocytoma and normal brain as
for example it is demonstrated for GDS1962
(GEO DataSet record 1962) file in Fig. 2. Real�
time PCR showed also slightly decreased IGF1
expression level (Fig. 3).
As it concerns IGF2 gene, SAGE revealed about
30�fold increased average expression level in
glioblastoma as compared to adult normal brain.
However, this increasing was not statistically signif�
icant (P = 0,293) due to the very high expression
levels in two of nine glioblastoma samples, much
more than the sample population median level. In
GEO repository, IGF2 gene set also consists of three
different probes corresponding to nucleotide
sequences in GeneBank: M17863, NM_000612
and X07868. In spite of some variations between
different probes, the results show mainly that in
average the expression level of IGF�II gene in
glioblastoma is increased slightly as compared to
anaplastic astrocytoma or normal brain (Fig. 4) and
1,6�fold increasing of average IGF�II expression in
glioblastoma as compared to human normal brain is
statistically significant (Table 3). Analysis of indi�
vidual DataSet files for each IGF2 probe showed
that glioblastomas can be divided on two subgroups:
one group has low expression level of IGF2 gene just
like normal brain samples, but other group was
characterized by significantly increased expression
of IGF2 gene (Fig. 5, a). This division could be seen
more distinctly if individual samples of 81 glioblas�
tomas and 23 normal brains, analyzed in GDS1962
file, to arrange according to IGF2 expression level in
descending order: approximately one quarter of
glioblastoma samples has increased IGF2 expres�
sion level while other three quarters of glioblastoma
samples have low expression level (Fig. 5, b). These
microarray data are in a good concordance with
results obtained by SAGE and were supported by
real�time (Fig. 3) and semi�quantitative RT�PCR
(Fig. 6).
IGF1 receptor is very well known target for
anti�cancer therapy [28]. However, SAGE revealed
only 1,4�fold not statistically significant increasing
of IGF1R expression (P = 0,510) and microarray
techniques showed even 1,2�fold (P = 0,046)
decreasing of its expression in glioblastoma as
compared to normal brain (Table 3). Real�time
RT�PCR (Fig. 3) revealed 1,7�fold increasing of
IGF1R expression, but the result was not statisti�
cally significant (P = 0,545). Thus, it can be con�
cluded that IGF1R expression do not differ signifi�
cantly in glial tumors and human normal brain.
Expression of insulin receptor (IR), which is used
alternatively by IGF2 [29], was decreased in 1,5�
fold in glioblastoma according to SAGE and
microarray results. At the same time, the expres�
sion of IGF2R gene was increased in glioblastoma
as compared to normal brain according to SAGE
ІSSN 0564–3783. Цитология и генетика. 2011. № 5 45
Expression of genes belonging to the IGF�system in glial tumors
Fig. 1. Comparison of IGF1 relative expression levels in
glioblastoma, anaplastic astrocytoma and human normal
brain according to microarray analysis data from six
DataSet files of GEO repository (indicated below the bars
in diagram). Data are presented for three probe sets of
IGF1 gene located on microarrays: AU14491 (a), M29644 (b)
and M37484 (c). Samples of normal brain indicated by
white bars, anaplastic astrocytomas – by grey bars, glioblas�
tomas – by dark bars
(3,3�fold, P = 0,053) and microarray analysis data
(1,9�fold, P < 0,001) (Table 3).
Comparison of IGFBP genes expression in
glioblastoma and normal brain by SAGE revealed
increased expression of all genes in glioblastoma
except IGFBP1 (Table 3). More than 3�fold up�
regulation of IGFBP2, IGFBP3, IGFBP4, IGFBP5,
and IGFBP7 genes in glioblastoma was statistically
significant (P < 0,05) and confirmed by data of
microarray analysis, which showed statistically sig�
nificant increased expression levels also for
IGFBP8 and IGFBP10 in addition to these five
genes. Decreased expression of remained three
genes (IGFBP1, IGFBP6 and IGFBP9) in glioblas�
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V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko et al.
Fig. 2. IGF1 expression in individual samples of glioblastoma, anaplastic astrocytoma and normal brain. Expression profile
for IGF1 gene (GeneBank: AU144912) obtained on the basis of the experimental data from DataSet record GDS1962 of
GEO repository, submitted by Sun et al. [24]
Table 3
Changes of the expression of IGF�system genes in glioblastoma according to three methods
Note. GB – glioblastoma, NB – normal brain. P�value below the chosen threshold P < 0.05 indicated in bold.
Gene name
SAGE
Average
GB NB
GB/NB P
Microarrays
Average
GB NB
GB/NB P
RT�PCR
Average
GB NB
GB/NB P
IGF1
IGF2
IGF1R
IGF2R
IR
IGFBP1
IGFBP2
IGFBP3
IGFBP4
IGFBP5
IGFBP6
IGFBP7
IGFBP8
IGFBP9
IGFBP10
0.1
66.4
3.1
9.7
2.4
1.4
34.3
26.8
19.2
165.6
13.4
269.8
106.3
0.6
37.6
0.0
11.2
2.2
3.0
3.4
2.4
5.6
7.2
0.8
26.0
8.8
10.2
10.2
0.0
6.6
1.14
0.19
0.83
1.31
1.17
0.62
0.77
0.77
1.02
0.64
1.20
0.64
0.52
1.60
0.41
1.07
0.65
0.88
1.24
1.15
1.17
2.00
1.32
1.18
1.73
1.14
0.95
0.89
1.45
1.30
<0.001
0.033
0.046
<0.001
<0.001
0.058
<0.001
<0.001
<0.001
<0.001
0.004
<0.001
<0.001
<0.001
<0.001
0.7
1.6
0.8
1.9
0.6
0.7
16.3
5.7
1.7
2.7
0.4
3.3
1.9
0.4
2.0
3.7
7.0
7.6
5.6
5.3
2.2
5.4
8.4
8.2
9.9
22.1
27.5
13.1
10.6
13.5
2.4
11.4
6.3
10.6
2.9
1.6
87.3
47.9
13.7
27.1
8.5
90.2
24.8
4.4
27.1
0.347
0.363
0.510
0.053
0.488
0.506
0.023
0.039
0.020
0.032
0.389
0.014
0.215
0.247
0.103
NaN
5.9
1.4
3.3
0.7
0.6
6.1
3.7
24.0
6.4
1.5
26.5
10.4
NaN
5.7
0.94
3.36
1.06
0.95
0.98
1.88
2.58
1.72
1.16
2.71
0.95
1.48
1.72
0.90
3.20
<0.001
0.052
0.006
<0.001
<0.001
0.008
<0.001
0.001
<0.001
0.072
<0.001
0.003
0.002
<0.001
0.001
toma according to the results of microarray analy�
sis in general were not in contradiction with SAGE
results which showed some statistically nonsignifi�
cant decrease of the expression for IGFBP1 or
increase of the expression for IGFBP6 and IGFBP9
(Table 3).
Results of the IGFBP genes expression analysis
by RT�PCR were in a quite good concordance
with SAGE and microarray data. Semi�quantitative
RT�PCR confirmed statistically significant increa�
sed expression of IGFBP2, IGFBP3, IGFBP4,
IGFBP7, IGFBP8, and IGFBP10 genes in glioblas�
toma (Fig. 6). Expression of IGFBP5 was increased
too, although P = 0,072. RT�PCR revealed also
increased expression of IGFBP1 gene in glioblas�
toma and this 1,88�fold increase was statistically
significant (Table 3). Unlike RT�PCR, SAGE and
microarray analysis results showed not statistically
significant decrease of IGFBP1 expression level in
glioblastoma. Expression of IGFBP6 and IGFBP9
genes was not changed significantly in glioblas�
toma according to the results of RT�PCR and this
in general does not contradict to SAGE and
microarray analysis, as mentioned above (Table 3).
ІSSN 0564–3783. Цитология и генетика. 2011. № 5 47
Expression of genes belonging to the IGF�system in glial tumors
Fig. 3. Analysis of IGF1 (a), IGF2 (b) and IGF1R (c) genes expression in glioblastoma and human normal brain by real�
tyme RT�PCR. Samples of normal brain indicated by white bars, glioblastomas – by dark bars
So, the expression of seven IGFBP genes
(IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP7,
IGFBP8, and IGFBP10) was increased in glioblas�
tomas according to three methods used for the
analysis. The results for IGFBP6 and IGFBP9 genes
differ slightly for three methods, but there were no
contrast differences between these results. It is
necessary to note that gene expression differences
found by microarray analysis were more statistical�
ly significant: p�values were below the chosen
threshold P < 0.05 for all genes analysed except
IGFBP1. This may be explained by larger sample
numbers in both glioblastoma and normal brain
groups analysed by this method as compared to
SAGE or RT�PCR.
Discussion. The central role that the IGF sys�
tem plays in initiating and promoting tumor pro�
gression makes it an attractive target for cancer
therapy. Various strategies have been used to target
components of this system in established animal
and human tumor cell lines and in animal models
of cancer; some of these strategies may be advanc�
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V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko et al.
Fig. 4. Comparison of the relative expression levels of IGF2 gene in glioblastoma, anaplastic astrocytoma and human normal
brain according to microarray analysis data from six DataSet files of GEO repository (are indicated below the bars in dia�
gram). Data are presented for three probe sets of IGF2 gene located on microarrays: M17863 (a), NM_000612 (b) and
X07868 (c). Samples of normal brain indicated by white bars, anaplastic astrocytomas – by grey bars, glioblastomas – by dark bars
ing to clinical use. Among them IGF1 was target�
ed by different strategies including IGF1 peptide
analogues [30], antisense oligonucleotides [31]
and triple helix�expressing vectors [32].
Although increased expression of IGF1, IGF2,
IGF1R or combinations thereof have been docu�
mented in various malignancies, these data show
that while a correlation between IGF1/IGF2
expression levels and tumor progression could be
consistently documented in some types of cancer
(e.g. colorectal, hepatocellular and pancreatic car�
cinomas), no consistent correlation was seen in
others (e.g. breast cancer) [4]. Taken as a whole,
these studies suggest that the IGF1 role in a
paracrine and/or autocrine promoting tumor
growth may vary depending on the tissue of origin.
ІSSN 0564–3783. Цитология и генетика. 2011. № 5 49
Expression of genes belonging to the IGF�system in glial tumors
Fig. 5. IGF2 expression in individual samples of glioblastoma, anaplastic astrocytoma and normal brain: a – expression
profile for IGF2 gene (GeneBank: X07868) obtained on the basis of the experimental data from DataSet record
GDS1962 of GEO repository, submitted by Sun et al. [24]; b – comparison of IGF2 expression in glioblastoma and normal
brain samples. Samples of normal brain indicated by white bars, glioblastomas – by dark bars
Moreover, in some cases, conflicting results were
obtained in different studies that analysed the
same types of malignant tumors (e.g. gliomas). The
references on IGF1 gene expressions in glioblastoma
are based on old papers, where authors used most�
ly slot blot hybridization or immunohistochemistry
on comparably small numbers of clinical samples
[5–10]. Immunohistochemical studies themselves
are not very convin�cing: authors only mention the
expression of IGF1 in primary human astrocy�
tomas [6] or write that IGFI mRNA can be seen in
both astrocytoma and non malignant control
human brain tissue [7]. The increased level of
IGF1 expression was mostly at the margin of
glioblastomas and in perivascular zone and so as it
was explained by authors [8, 9], could not be seen
when the total RNA from the whole tumor was
taken for IGFI mRNA measurement.
On the other hand, the expression of IGF1 gene
in astrocytic tumors was not found when we used
SAGE or analysed data from the GEO repository.
These data show that IGF1 gene is expressed at a
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V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko et al.
Fig. 6. Semi�quantitative PCR�analysis of IGF system genes expression in glioblastomas and normal brain. Control gene,
ACTB, was used to determine relative expression level of analyzed genes in indivdual samples. Tissue and tumor types are
indicated above each lane of the electrophoresis, numbers are the conditional numbers of RNA samples. GB – glioblastoma,
NB – human normal brain, K(–) – control reaction without cDNA
low level in normal adult human brain and this
level was not increased in glioblastoma. As it was
mentioned above, other investigations also did not
show the increased IGF1 gene expression in this
tumor [9, 10]. Taking into account quite big number
of samples and different methods used in present
investigation, the results of this study indicate that
increasing of IGF1 gene expression may be involved
only in the formation of the limited part of astro�
cytic gliomas. Although the IGF1 was proposed as
one of targets for glial tumor therapy and was sup�
posed to become the alternative treatment for
human glioblastoma [33], our results show why the
anti�IGF1 treatment may not give positive results
with gliomas, supposing that the development of
these tumors is activated by some other way.
In contrast to IGF1, the expression of IGF2 gene
is up�regulated in glioblastoma although its
expression level is relatively low as it was found
previously in our work [34] as well as in other pub�
lications [35, 36]. Microarray analysis data show
clearly the existence of the separate group of the
glioblastomas overexpressing IGF2 gene. This is in
agreement with the results of Soroceanu et al. [37]
who found that among 165 primary high�grade
astrocytomas, 13 % of glioblastomas and 2 % of
anaplastic astrocytomas expressed IGF2 mRNA at
the levels >50�fold the sample population median.
Authors found that IGF2 can substitute for EGF
to support the growth of glioblastoma�derived
neurospheres and growth�promoting effects of
IGF2 were mediated by the IGF1 receptor and
phosphoinositide�3�kinase regulatory subunit 3
(PIK3R3), a regulatory subunit of PI3K.
Survey of published data revealed only two old
publications in which the author reported about
the fourfold increase of IGF2 receptor, but not
IGF1 receptor [38] or 2� to 5�fold higher cellular
concentration of IGF2 receptor than the amount
of IGF1 receptor [39]. Thus, IGF1 participation
in cellular signaling pathways of glioblastoma may
be substituted by IGF2 which may also stimulate
both main signaling pathways, regulated by the
extracellular signal�regulated kinase (ERK1/2)
and protein kinase B�mediated (AKT).
When viewed together, all studies concerning
the role of IGFs and IGF1R expression levels per
se as indicators of tumor stage or predicators of
disease outcome defy simple generalization and
may be highly tumor�type specific. However as dis�
cussed above, the relevance of the IGF axis to can�
cer progression cannot be fully estimated by analysis
of the expression levels of the IGF1R and its lig�
ands only, because activation of the signaling path�
way may occur through alternative mechanisms that
bypass the requirement for receptor and/or ligand
upregulation. For example, product of chitinase 3�
like 1 (CHI3L1, other names HC gp�39 or YKL�40)
gene with significantly increased level in glioblas�
toma [40] may also stimulate ERK1/2� and AKT�
signaling pathways in a concentration range similar
to the effective dose of IGF1. Just as IGF1, it acti�
vates two signal cascades, regulated by ERK1/2 and
AKT and associated with mitogenesis control [41].
Results of the analysis of IGFBP genes expres�
sion in glioblastoma, obtained with three methods,
demonstrate up�regulation of the majority IGFBPs
in this tumor. Increased expression of IGFBP2 [21,
42–48], IGFBP3 [44, 47, 49, 50], IGFBP4 [21, 49],
IGFBP5 [44, 48–50], IGFBP6 [21, 44, 49], IGFBP7
[51], and IGFBP8 [44] genes in glioblastoma was
reported previously in the studies using microarray
analysis. It was shown that overexpression of
IGFBP5 gene correlates with the histological grade
of human diffuse glioma: 83 % (58/70) of glioblas�
tomas (WHO Grade IV) were immunopositive for
IGFBP5, which was significantly higher than
WHO Grade III gliomas (41 %, 41/101) or WHO
Grade II gliomas (18 %, 13/72) (p < 0.001) [52].
Expression of IGFBP1 to IGFBP6 was analysed by
PCR in glioblastoma cell lines T98G, A172,
86HG39 and U87MG and expression of IGFBP2�
IGFBP6 was found in all cell lines [36]. Higher
content of IGFBP1 mRNA in primary gliomas was
demonstrated only in one work [53]. Authors found
by RT�PCR that expression level of IGFBP1 gene
did not depend on grade of tumor malignancy.
Produced in tumor cells IGFBPs may stabilize
insulin�like growth factor (s), IGF1 and/or IGF2,
and drive their activation in glial tumors. On the
other hand, some of the IGFBPs inhibit IGF
actions or may act by a mechanism independent of
IGFs, as reviewed by Mohan and Baylink [16]. It
was documented that IGFBP1 increased migration
of Chinese hamster ovary cells and trophoblast cells
and affected apoptosis of breast cancer cells inde�
pendently of IGF1 by activating α5β1 integrin–
FAK–ILK–PI3�K–Akt signaling cascade [54].
Function of other inhibitory protein, IGFBP2,
could be complex depending on the cell type and
ІSSN 0564–3783. Цитология и генетика. 2011. № 5 51
Expression of genes belonging to the IGF�system in glial tumors
cellular microenvironment. As reviewed by Fuku�
shima and Kataoka [55], IGFBP2 has been con�
sidered as an inhibitory factor of IGF actions, parti�
cularly of IGF2, but binding of the IGFBP2/IGF
complex to cellular surface proteoglycan may
result in concentration of IGFs on the cell surface
thus enhancing their actions. Authors supposed,
that since binding of IGFs by IGFBP2 has
growth�and/or migration�inhibitory effects, other
mechanisms must be taken into account if attempt
to find the correlation between overexpression of
IGFBP2 and malignant phenotypes of glioblas�
toma and proposed that IGFBP2 exerts influence
on stimulation of cell proliferation and/or migra�
tion in an IGF�independent manner. Other study
supported this suggestion and provided definitive
evidence that IGFBP2 plays a key role in activa�
tion of the AKT pathway and collaborates with K�
Ras or platelet derived growth factor B (PDGFB)
in the development and progression of astrocytoma
and oligodendroglioma [56].
IGFBP3 is known to block IGF action and
inhibit cell growth. In addition, it possesses both
growth�inhibitory and �potentiating effects on cells
that are independent of IGF action and are medi�
ated through specific IGFBP3 binding proteins/
receptors located at the cell membrane, cytosol, or
nuclear compartments and in the extracellular
matrix. Transferrin and type I alpha collagen were
characterized as these IGFBP3 binding proteins
[57, 58]. IGFBP3 was found among hypoxia�
induced genes by the comparison of gene expres�
sion profiles of the U251 malignant glioma cell
line under normoxic and hypoxic conditions, but
the role of increased expression of IGFBP3 gene in
glioma tumorigenesis is unclear [59].
It was revealed that IGFBP4, a negative modu�
lator of IGF1, displayed IGF1�independent anti�
angiogenic effect on glioblastoma cells in response
to their treatment by dibutyryl cyclic AMP (dB�
cAMP) [60].
IGFBP5 could also stimulate cell migration
through interaction with cell surface heparin sul�
fate proteoglycans and to determine cell fates by
regulating apoptotic molecules (bax, bcl�2) and
activating p38 MAP kinase and ERK 1/2 signal
transduction pathways [61].
IGFBP6 is a relatively specific inhibitor of
IGF2 actions. Overexpression of IGFBP6 inhibits
tumor growth by inducing apoptosis and recently
IGFBP6 was listed as a marker for cell senescence
because it produces growth arrest with features of
senescence but without the expression of cell dif�
ferentiation markers [62].
IGFBP7 plays a negative role in the growth of
cancer cells, including breast cancer, human
prostate cancer, human cervical carcinoma (HeLa),
murine embryonic carcinoma (P19), and osteosar�
coma (Saos�2) cells [63]. Expression of IGFBP7 has
been found to be up�regulated in human colorec�
tal cancer and glioma cell lines and down�regulat�
ed in prostate and breast cancer cells. IGFBP7 is
exclusively associated with laminin�stained glioblas�
toma vessels but was not observed in the vessels
from nonmalignant brain [51]. IGFBP7 regulated
glioma LN18 and LN443 cells proliferation and
growth but not cell survival and promoted the
migration of these cells through regulating the AKT
(decreased phosphorylation) and ERK1/2 (enhan�
ced phosphorylation) signal transductions [64].
IGFBP8(CTGF), IGFBP9(NOV) and IGFBP10
(CYR61) belong to the family of genes encoding
CCN (cysteine�rich CYR61/CTGF/nephroblas�
toma�overexpressed gene) proteins which has been
shown to play an important role in many processes,
including proliferation, migration, adhesion, extra�
cellular matrix regulation, angiogenesis, tumorige�
nesis, fibrosis, and implantation. CCN proteins
share a modular structure and have in their N�ter�
mini four conserved domains with sequence
homologies to insulin�like growth factor binding
proteins (IGFBPs) [65]. Expression of these three
genes was analysed by real�time PCR in gliomas of
different malignancy grades and normal human
brain by Xie et al. [66]. Authors found enhanced
expression of IGFBP8 (CCN2) in 31 and IGFBP10
(CCN1) in 27 from 40 glioblastomas analysed, while
only 7 glioblastomas had high levels of IGFBP9
(CCN3) mRNA. Significant correlation existed
between IGFBP8 and IGFBP10 mRNA levels with
tumor grade and survival of glioblastoma patients ,
but statistical analysis showed no difference between
the clinical and pathological features and expression
level of IGFBP9 in gliomas. Results obtained in
this work suggest that IGFBP8 and IGFBP10 may
play some role in the progression of gliomas, but
IGFBP9 is involved neither in their development
nor progression. Furthermore, IGFBP9 had antipro�
liferative activity and suppressed the growth of
glioma cells [67]. It was shown that IGFBP8 (CTGF)
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V.V. Dmitrenko, V.M. Kavsan, O.I. Boyko et al.
was associated with oncogenic activities and drug
resistance in glioblastoma. Overexpression of
IGFBP8 caused the U343 glioblastoma cells to
survive for longer than 40 days in serum�free
medium and resist antitumor drugs including
tumor necrosis factor (TNF), TNF�related apop�
tosis�inducing ligand, VELCADE (bortezomib,
proteasome inhibitor) and temozolomide [68]. Xie
et al. [69] demonstrated that IGFBP10 acts as an
oncogene through the integrin�linked kinase
(ILK) to stimulate β�catenin�TCF/LEF and AKT
signaling pathways. Authors showed that forced
expression of IGFBP10 in U343 glioblastoma cells
accelerated their growth in liquid culture,
enhanced their anchorage�independent prolifera�
tion in soft agar, and significantly increased their
ability to form tumors in nude mice.
As a summary, we have shown that IGF1 gene
expression is increased only in few cases of
glioblastoma but predominantly it is not higher
that in normal brain. IGF1 participation in cellu�
lar signaling pathways of glioblastoma may be sub�
stituted by increasing expression of IGF2 or
IGF1R, which may also stimulate both main sig�
naling pathways, regulated by ERK1/2 and AKT.
Several other genes with significantly increased
expression may also stimulate these pathways in
glioblastoma. Up�regulated IGFBPs may activate
IGF, even if the latters do not increase their expres�
sion leading to the anti�apoptotic consequences in
glial tumors. On the other hand, increased produc�
tion of some IGFBPs leads to enhance their IGF�
independent effects which may play an important
role in the development of gliomas.
Obtained results highlight the importance of
viewing the IGF�related proteins as a complex
multifactorial system and show that changes in the
expression levels of any one component of the sys�
tem, in a given malignancy, should be interpreted
with caution. Similar to the experience with other
biology�based therapies, effective targeting of the
IGF system may require a customized approach,
where tumor profiling guides the selection of the
appropriate drugs. As targeting of the IGF�family
members for anti�cancer therapy is rapidly becom�
ing clinical reality, an understanding of this com�
plexity is very timely.
This work was supported in part by National
Academy of Sciences of Ukraine in frames of the pro�
gram «Fundamental grounds of molecular and cell
biotechnologies» and by Science and Technology
Center in Ukraine, project 4688.
В.В. Дмитренко, В.М. Кавсан, О.И. Бойко,
В.И. Рымарь, А.А. Степаненко, O.В. Балынская,
Т.А. Малышева, В.Д. Розуменко, Ю.А. Зозуля
ЭКСПРЕССИЯ ГЕНОВ, ОТНОСЯЩИХСЯ
К IGF�СИСТЕМЕ, В ГЛИАЛЬНЫХ ОПУХОЛЯХ
Повышенныe уровни экспрессии отдельных чле�
нов семейства инсулиноподобных факторов роста
(IGF) – IGF1 и IGF2, IGF�рецепторов, IGF�связыва�
ющих белков или их комбинации были обнаружены
в различных новообразованиях, включая глиомы. Ре�
зультаты множественных исследований свидетельст�
вуют о том, что инсулиноподобные факторы роста мо�
гут стимулировать рост опухоли in situ аутокринным
и/или паракринным способом, однако это действие
может варьировать в зависимости от тканевого проис�
хождения опухоли. Усилениe экспрессии гена IGF1
не было найдено в глиобластомах и предполагается,
что участие IGF1 в развитии глиальных опухолей мо�
жет быть замещено белковыми продуктами экспресси�
рующихся на высоком уровне генов, также участвую�
щими в cигнальных путях MAPK и PI3K. Повышенный
уровень экспрессии генов IGF�связывающих белков
(IGFBP) в опухолях головного мозга делает картину
еще более сложной. Как и другие связывающие белки,
IGFBP регулируют активность своих лигандов, прод�
левая время их полужизни. B cтaтьe oбсуждаются про�
тиворечивыe результаты, oпиcaнныe различными ла�
бораториями для глиом. Пoлучeнныe данные демон�
стрируют важность рассмотрения белков семейства
инсулиноподобных факторов роста как сложную муль�
тифункциональную систему и показывают, что изме�
нения в уровне экспрессии любого компонента системы
в упомянутой опухоли должны интерпретироваться с
предосторожностью. В связи с тем, что выбор членoв
IGF�ceмeйcтвa в качестве мишени для противоопухо�
левой терапии быстро приобретает клиническую ре�
альность, понимание сложноcти этой системы явля�
ется весьма своевременным.
В.В. Дмитренко, В.М. Кавсан, О.І. Бойко,
В.І. Римар, О.А. Степаненко, O.В. Балинська,
Т.А. Малишева, В.Д. Розуменко, Ю.П. Зозуля
ЕКСПРЕСІЯ ГЕНІВ,
ЩО НАЛЕЖАТЬ ДО IGF�СИСТЕМИ,
У ГЛІАЛЬНИХ ПУХЛИНАХ
Підвищений рівень експресії окремих членів роди�
ни інсуліноподібних факторів росту (IGF) – IGF1
та IGF2, IGF�рецепторів, IGF�зв’язуючих білків або
їхньої комбінації був знайдений у різних новоутворен�
нях, включаючи гліоми. Результати множинних до�
ІSSN 0564–3783. Цитология и генетика. 2011. № 5 53
Expression of genes belonging to the IGF�system in glial tumors
сліджень свідчать про те, що інсуліноподібні фактори
росту можуть стимулювaти ріст пухлини in situ ауто�
кринним та/або паракринним способом, однак ця дія
може варіювати в залежності від тканинного походжен�
ня пухлини. Посилення експресії гена IGF1 не було
знайдено в гліобластомах і передбачається, що участь
IGF1 у розвитку гліальних пухлин може бути замінена
білковими продуктами генів, що експресуються на
високому рівні, які також приймають участь у cигналь�
них шляхах MAPK та PI3K. Підвищений рівень екс�
пресії генів IGF�зв’язуючих білків у пухлинах голов�
ного мозку робить картину ще більш складною. Як
і інші зв’язуючі білки, IGF�зв’язуючі білки регулюють
активність своїх лігандів, продовжуючи час їхнього
півжиття. У cтaттi oбговорюються суперечливi резуль�
тати, опиcанi різними лабораторіями для гліом. Oтри�
манi дані демонструють важливість розгляду білків ро�
дини інсуліноподібних факторів росту як складну
мультифункціональну систему і показують, що зміни
рівня експресії будь�якого компонента системи у да�
ній пухлині повинні інтерпретуватися із пересторо�
гою. В зв’язку з тим, що вибір членiв IGF�ciмeйcтвa
як мішені для протипухлинної терапії швидко набуває
клінічної реальності, розуміння цієї системи є вельми
своєчасним.
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Expression of genes belonging to the IGF�system in glial tumors
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