DIFFERENTIAL EXPRESSION OF FGFRs SIGNALING PATHWAY COMPONENTS IN BLADDER CANCER: A STEP TOWARD PERSONALIZED MEDICINE
Ousati Ashtiani Z, Tavakkoly-Bazzaz J, Salami SA, Pourmand MR, Mansouri F, Mashahdi, 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
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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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