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
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INTRODUCTION
Bladder cancer (BC) is one of the most common types
of urinary system cancers in men, and with less frequency,
in women worldwide [1]. It is a complex disease resulting
from both genetic and environmental factors. Aberrations
in different genes’ structure and function, molecular derangements,
and several environmental factors have been
found to play a crucial role in the development of BC. Age,
increased body mass index (BMI), occupation, unhealthy
diet, and some drugs can increase the risk of BC development
[2]. The epigenetic mechanism also involves in BC
tumorigenesis [3]. Blood cancers are generally classified as
non muscle invasive with low-grade (pTa/T1) and muscle
invasive (pT2-4) that are frequently high-grade tumors [4].
Regulation of different processes during cell cycles,
including cell growth, differentiation, cell movement, and
apoptosis are orchestrated by diverse signaling pathways.
When the above mentioned processes are dysregulated
secondary to changes in a key genetic element of cellular
homeostasis, tumorigenesis can be the outcome. The fibroblast growth factor receptor (FGFR) signaling pathway
has been receiving growing attention as one of the major
contributors in cell cycle regulation that in turn, introduces
this specific molecule as a potential drug target for cancer
therapy [5-7].
The mammalian fibroblast growth factors (FGFs) are
a family of growth factors, consisting of 18-22 members
that play an essential role in multiple physiological events
such as angiogenesis, wound healing, embryonic development,
and various endocrine signaling pathways both in
health and disease. Fibroblast growth factors signaling
dysregulation is evidently present in a considerable number
of BC cases [8]. A subfamily of receptor tyrosine kinases
(RTKs) named fibroblast growth factor receptor family
comprises of four members (FGFR1-4). They are activated
by binding to their ligand FGFs, which results in kinase
activation. Different changes exemplified by FGFRs mutations
and translocations, as well as alterations in mRNA
splicing and gene amplification of FGF/FGFR pathway
and protein expressions levels have been documented in
different cancers [9-14]. Aberrations of the FGFR signaling
pathway can activate downstream pathways, PI3K/
AKT, MAPK signaling cascade, those which contribute
to tumor progression. The FGFR1 and FGFR3 mutations
and over expression have been reported in BC [15-18],
while FGFR3 alterations were significantly involved in
the pathogenesis of urothelial carcinoma (UC) as a whole.
However, its clinicopathological implications and significance
have not so far been well addressed, especially in
the case of muscle-invasive BCs [19]. In contrast to the
non muscle invasive UC, where the FGFR3 is frequently
mutated or overexpressed, in muscle invasive forms the
incidence of FGFR3 mutation and mRNA/protein expression
changes remain unknown [20]. The FGFR1 gene
expression alteration is also related to certain cancers [8,9,
14]. More notably, a recent study using next generation
sequencing in advanced BC has demonstrated a gene fusion
of FGFR1 and NTM (FGFR1-NTM) [21].
Molecular genetic studies on FGFR1 and FGFR3
have revealed the role of these gene changes in different
cancers and their value in molecule-targeted therapy.
The present study was conducted because of a significant
heterogeneity in response of the BC cells to FGFR inhibitors
that highlights the importance of the personalized
medicine, and also with regard to the remarkable
inter-individual variations between different populations.
For the first time, this study designed to evaluate FGFR1
and FGFR3 expressions at the mRNA level, and their associations
with grade, stage and other clinicopathological
features in Iranian subjects with BCs.
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