We discovered a positive feedback loop, in which the activation of p38 and AKT downstream from the altered FGFR3 upregulates <i>MYC</i> mRNA levels and stabilizes MYC protein, respectively, leading to the accumulation of MYC, which directly upregulates <i>FGFR3</i> expression by binding to active enhancers upstream from <i>FGFR3</i> Disruption of this FGFR3/MYC loop in bladder cancer cell lines by treatment with FGFR3, p38, AKT, or BET bromodomain inhibitors (JQ1) preventing <i>MYC</i> transcription decreased cell viability <i>in vitro</i> and tumor growth <i>in vivo</i> A relevance of this loop to human bladder tumors was supported by the positive correlation between <i>FGFR3</i> and <i>MYC</i> levels in tumors bearing <i>FGFR3</i> mutations, and the decrease in FGFR3 and MYC levels following anti-FGFR treatment in a PDX model bearing an <i>FGFR3</i> mutation.
Whole-genome and whole-exome sequencing of bladder cancer identifies frequent alterations in genes involved in sister chromatid cohesion and segregation.
Here we show that HDAC6 loss or inhibition reduces FGFR3 accumulation in cells made tumorigenic by ectopic expression of a mutant activated version of FGFR3 together with the MYC oncoprotein and in a bladder cancer cell line whose tumorigenicity is dependent on expression of a translocated version of FGFR3.
The phenotypic consequences of constitutive activation of FGFR3 in bladder cancer have not been elucidated and further studies are required to confirm the consequences of inhibiting receptor activity in urothelial cells.
Recent developments in the field of molecular mutational pathway analyses based on next generation sequencing technology together with classic data derived from the description of mutations in the FGFR3 (fibroblast growth factor receptor 3) gene, mutations on TP53 gene, and cDNA technology profiling data gives support to a differentiated taxonomy of bladder cancer.
Knockdown of endogenous FGFR3 impaired the activity of daidzein against bladder cancer, which suggested that the effect of daidzein was mainly mediated by FGFR3 pathway.
This is a comprehensive genomic characterization of 40 urothelial bladder carcinoma (UBC) cell lines including information on origin, mutation status of genes implicated in bladder cancer (FGFR3, PIK3CA, TP53, and RAS), copy number alterations assessed using high density SNP arrays, uniparental disomy (UPD) events, and gene expression.
When we examined detailed data on a prevalent occupational exposure associated with increased bladder cancer risk, straight metalworking fluids, we also observed statistically significant additive interaction for rs798766 (TMEM129-TACC3-FGFR3, P interaction = .02), with the interaction more apparent in patients with tumors positive for FGFR3 expression.All statistical tests were two-sided.
Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer.
The identification of mutations of FGF receptor 3 (FGFR3) in most noninvasive bladder tumors and the recent finding of overexpression of this receptor not only in superficial tumors but also in many invasive bladder cancers has generated optimism that therapies targeting this receptor tyrosine kinase may have major application in the treatment of urothelial cancers.
In bladder carcinoma, we recently identified FGFR3 mutations in 41% of tumours, making this the most frequently mutated putative oncogene identified in bladder cancer to date.
FGF receptor-3 (FGFR3) is a drug target in a subset of human multiple myelomas (MM) and is mutationally activated in some cervical and colon and many bladder cancers and in certain skeletal dysplasias.
This study indicates that the FGFR3 urine assay, which was originally developed to monitor bladder cancer, is also a useful tool for diagnosing upper urinary tract cancer in a real-life setting.