DIFFERENTIAL EXPRESSION OF FGFRs SIGNALING
PATHWAY COMPONENTS IN BLADDER CANCER:
A STEP TOWARD PERSONALIZED MEDICINE
Ousati Ashtiani Z1,2, Tavakkoly-Bazzaz J2,*, Salami SA3,
Pourmand MR4, Mansouri F5,6, Mashahdi R1, Pourmand G1,*
*Corresponding Author: Professor Gholamreza Pourmand, Urology Research Center, Sina Hospital, Tehran University Medical Sciences,
Hasan Abad Square, Tehran, 113746911, Iran. Tel: +98-216-634-8560. Fax: +98-216-634-8561. Email: pourmand@tums.ac.ir and/
or Associate Professor Javad Tavakkoly-Bazzaz, Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences,
Poursina Street, Tehran, 1417613151, Iran. Tel: +98-218-895-3005. Fax: +98-218-895-3005. Email: tavakkolybazzazj@tums.ac.ir
page: 75
|
|
DISCUSSION
This is the first study that demonstrates FGFR1 and
FGFR3 mRNA expression levels in Iranian patients with
BCs. The FGF/FGFR pathway is one of the central mechanisms
that govern differentiation, proliferation, survival
and many other issues of cellular characteristics. Large
number of evidence supports the appropriate functionality
of FGFs-FGFRs systems is dysregulated at any point
within their signaling cascade that could frequently lead
to cancer development via activation of the downstream
pathway [22].
The FGFs and FGFRs changes at different levels
featured by gene mutations, gene fusions and aberrant
expressions or amplification have been identified in the
progression of UCs [8,21]. Such aberrations in FGFR3
are one of the most common molecular events in UCs,
but some of them such as gene amplification are relatively
rare [23,24]. Preclinical studies weighed the applicability
of FGFR3 for targeted therapy [25]. In this pilot study,
FGFR3 mRNA over expression was observed in the majority
of all subjects (shaped mainly by high grade or muscle
invasive tumors) (92.0%), while most of the previous studies
were conducted in cases with non muscle invasive
tumors [20, 26]. The frequency of FGFR3 mRNA over
expression between the subjects of the present study was
clearly higher than that of previous reports in BC [20].
Analyses of our data showed that FGFR3 mRNA over
expression was associated with smoking and family history
(p = 0.037, p = 0.004, respectively). This FGFR3 tumoral
over expression was not related to the other clinicopathological parameters including tumor grade or stage. Since
up- and down-regulation of FGFRs have been found in
the context of different cancers [10,19,28,29], it is suggested
that the potential oncogenic and tumor suppressive
influencing FGFRs can be implemented by either its up- or
down-regulation according to the nature and stages/grades
of the tumors. Mainly mediated by FGFR3 gene mutations,
over expression of FGFR3 mRNA and protein levels have
been evident frequently in different cancers, which may
suggest more clearly its oncogenic properties [10,22,27].
In the current study, increased expression of FGFR3 in
most of the tumor tissues, regardless of their grade, stage
and type, suggest the importance of the FGFR3 role as
a driving member for tumor growth and progression in
Iranian BC subjects.
In terms of FGFR1 expression patterns, to some extent,
our results are not consistent with previous reports.
We observed decreased mRNA expression of FGFR1 in
60.0% of cases, of which the majority of them had highgrade
BC (p = 0.01), while previous studies found an increased
expression of both mRNA and protein in mostly
non invasive BC [9,20,24,29]. However, in another study
that was conducted on an invasive form of BC, the level
of FGFR1 was significantly up-regulated [18]. This discrepancy
may be partly attributed to geographical and
methodological parameters including technical issues as
well as histopathological heterogeneity within individual
tumor type and also proportion of case within various
grade and stage classes.
While the pivotal role of the FGFR1 gene in the development
of different types of cancer is suggested by
several studies, it seems the underlying mechanism for
FGFR1 gene involvement or the pattern of its dysregulated
expression is not fixed. For example, it is reported that the
main reason for FGFR1 up-regulation in breast cancer is
the amplification of the FGFR1 gene at the genome level
that could be evidenced by high FGFR1 expression level in
breast tumors [30], whereas we mentioned before, it seems
that the amplification of FGFRs genes is not the case in
BC. In addition to BC, the reduced expression of FGFR1
is also evident in some other types of cancers, such as parathyroid
cancer [14]. Such decreased expression patterns,
which may suggest a potential tumor suppressive role for
FGFRs, was also reported for FGFR2 in several cancers
including bladder, liver, salivary gland and prostate; but
the exact mechanism remains unknown [22].
However, it is so complicated to find out which member
of the FGFRs system is playing the central role in
cancer. Cheng et al. [29] stated that FGFR3 plays a more
important role than FGFR1in stimulating BC tumor cell
proliferation. Our data indicates that reduced mRNA expression
of FGFR1 is associated with high-grade tumors,
contrasted by its increased expression in low-grade tumors.
This would suggest that although FGFR1 is less important
than FGFR3 in BC cell proliferation, up-regulation of
FGFR1 expression can be considered as an early event,
the same as FGFR3, in the initiation and development of
BC that was also raised by some previous reports [18,31].
In this regard, increased expression of FGFR1 and FGFR3
proteins are reported in the early stages of non small cell
lung cancer [13].
In addition, it seems that FGFRs act differentially
depending on the tumor’s type that could explain that
contradictory results may be partly due to the cell type
specificity. For instance, in cervical cancer, expression
of FGFR1, FGFR2 and FGFR4 were higher in cancerous
tissues, whereas FGFR3 was higher in non cancerous
tissues [27]. In addition to cell specificity, alternative
splicing of the extracellular fragment of FGFR1-3 may
be partly accountable for this discrepancy. Alternative
splicing can result in the formation of isoforms, which in
turn, change ligand-binding specificity and the switching
of the cross-talk between isoforms. This, in turn, causes
alterations in FGFR signaling leading to influences on
downstream signaling cascades. It has been reported that
two splice variants of FGFR1 gene called FGFR1α and
FGFR1β were expressed at similar levels in normal urothelial
cells, but expression level of FGFR1β in tumor
cells were higher than in controls. They also presented
that FGFR1β: FGFR1α ratio was significantly increased in
relation to tumor stage and grade (31). On the other hand,
the epigenetic process alterations are thought to influence
gene expression largely at the transcription level [32], it
may be considered as a reason for this inconsistency in
different studies.
To the best of our knowledge, this pilot study is the
first report examining the expression of two components
of FGFR signaling pathway (FGFR1, FGFR3) in Iranian
BC subjects in order to find out whether they can be
used as a molecule for targeted interventions. The present
study showed that lower mRNA expression of FGFR1
was significantly associated with high-grade tumors and
in low-grade tumors increased expression was observed.
Our results suggest that the expression mode of FGFR1
is somehow related to the cancer grade. With regard to
FGFR1 over expression in low-grade tumors and FGFR3
over expression in both high- and low-grade tumors, it is
probable that these components of FGFR signaling cascade
may be considered distinctly as potential candidates for
targeted therapy. However, under individualized medicine strategy for
BC in the future, it seems that FGFRs could provide attractive
targets for therapeutic interventions. Because of the heterogeneity
between different populations, such objective requires
a more comprehensive understanding on the role of FGFRs
in BC, coupling with the data on larger sample sizes of the
cases and controls. Finally, it is very crucial to remember
that the inter-individual phenotypic variation at the cellular
and molecular level is not solely dictated by genetic impressions.
Accordingly, epigenetic issues, which themselves are
influenced by environmental factors, should be taken into
account to unravel the reality behind these observations.
|
|
|
|
 |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
|
