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MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer

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 s...

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Autores principales: Drayton, Ross M., Peter, Stefan, Myers, Katie, Miah, Saiful, Dudziec, Ewa, Bryant, Helen E., Catto, James W. F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171637/
https://www.ncbi.nlm.nih.gov/pubmed/25071007
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author Drayton, Ross M.
Peter, Stefan
Myers, Katie
Miah, Saiful
Dudziec, Ewa
Bryant, Helen E.
Catto, James W. F.
author_facet Drayton, Ross M.
Peter, Stefan
Myers, Katie
Miah, Saiful
Dudziec, Ewa
Bryant, Helen E.
Catto, James W. F.
author_sort Drayton, Ross M.
collection PubMed
description 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.
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spelling pubmed-41716372014-09-23 MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer Drayton, Ross M. Peter, Stefan Myers, Katie Miah, Saiful Dudziec, Ewa Bryant, Helen E. Catto, James W. F. Oncotarget Research Paper 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. Impact Journals LLC 2014-07-15 /pmc/articles/PMC4171637/ /pubmed/25071007 Text en Copyright: © 2014 Drayton et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Drayton, Ross M.
Peter, Stefan
Myers, Katie
Miah, Saiful
Dudziec, Ewa
Bryant, Helen E.
Catto, James W. F.
MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer
title MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer
title_full MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer
title_fullStr MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer
title_full_unstemmed MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer
title_short MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer
title_sort microrna-99a and 100 mediated upregulation of foxa1 in bladder cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171637/
https://www.ncbi.nlm.nih.gov/pubmed/25071007
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