title: MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer.
abstract: Urothelial cell carcinoma of the bladder (UCC) is a common disease often characterized by FGFR3 dysregulation. Whilst upregulation of this oncogene occurs most frequently in low-grade non-invasive tumors, recent data reveal increased FGFR3 expression characterizes a common sub-type of invasive UCC sharing molecular similarities with breast cancer. These similarities include upregulation of the FOXA1 transcription factor and reduced expression of microRNAs-99a/100. We have previously identified direct regulation of FGFR3 by these two microRNAs and now search for further targets. Using a microarray meta-database we find potential FOXA1 regulation by microRNAs-99a/100. We confirm direct targeting of the FOXA1 3'UTR by microRNAs-99a/100 and also potential indirect regulation through microRNA-485-5p/SOX5/JUN-D/FOXL1 and microRNA-486/FOXO1a. In 292 benign and malignant urothelial samples, we find an inverse correlation between the expression of FOXA1 and microRNAs-99a/100 (r=-0.33 to -0.43, p<0.05). As for FGFR3 in UCC, tumors with high FOXA1 expression have lower rates of progression than those with low expression (Log rank p=0.009). Using global gene expression and CpG methylation profiling we find genotypic consequences of FOXA1 upregulation in UCC. Genetic changes are associated with regional hypomethylation, occur near FOXA1 binding sites, and mirror gene expression changes previously reported in FGFR3 mutant-UCC. These include gene silencing through aberrant hypermethylation (e.g. IGFBP3) and affect genes characterizing breast cancer sub-types (e.g. ERBB2). In conclusion, we have identified microRNAs-99a/100 mediate a direct relationship between FGFR3 and FOXA1 and potentially facilitate cross talk between these pathways in UCC.
authors: Academic Unit of Molecular Oncology, University of Sheffield, UK.
authors: Ross M
authors: RM
authors: Drayton
authors: Academic Unit of Molecular Oncology, University of Sheffield, UK.
authors: Stefan
authors: S
authors: Peter
authors: Academic Unit of Molecular Oncology, University of Sheffield, UK.
authors: Katie
authors: K
authors: Myers
authors: Academic Unit of Molecular Oncology, University of Sheffield, UK; Academic Urology Unit, University of Sheffield, UK.
authors: Saiful
authors: S
authors: Miah
authors: Academic Unit of Molecular Oncology, University of Sheffield, UK; Academic Urology Unit, University of Sheffield, UK.
authors: Ewa
authors: E
authors: Dudziec
authors: Academic Unit of Molecular Oncology, University of Sheffield, UK.
authors: Helen E
authors: HE
authors: Bryant
authors: Academic Unit of Molecular Oncology, University of Sheffield, UK; Academic Urology Unit, University of Sheffield, UK.
authors: James W F
authors: JW
authors: Catto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C544266:MIRN100 microRNA, human; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3