title: Analysis of the Polycomb-related lncRNAs HOTAIR and ANRIL in bladder cancer.
abstract: BACKGROUND
  Long non-coding RNAs (lncRNAs) have been claimed as key molecular players in gene expression regulation, being involved in diverse epigenetic processes. They are aberrantly expressed in various tumors, but their exact role in bladder cancer is still obscure. We have recently found a major role of the Polycomb repression complex in recurrence of non-muscle-invasive bladder cancer. Here, we report the xpression of Polycomb-related lncRNAs:antisense noncoding RNA in the INK4 locus (ANRIL) and HOX antisense intergenic RNA (HOTAIR) in these tumors.
  
  
  RESULTS
  We studied a dataset of non-invasive bladder cancer samples by quantitative reverse transcription PCR (RT-qPCR) and analyzed also invasive bladder cancer samples using TCGA data. Our results showed that, while ANRIL seemed not to have a determining role, an increased HOTAIR expression appeared in recurrent and high-graded tumors associated with poor prognosis. In addition, through genome-wide transcriptome analyses, we observed that HOTAIR-EZH2-complex-regulated genes can efficiently discriminate between non-tumoral, recurrent, and non-recurrent bladder cancer samples. We also observed a significant correlation between EZH2 and HOTAIR expression levels. Using overexpression, knockdown, and pharmacological approaches in bladder cancer cell lines, we also observed that EZH2 regulates HOTAIR expression.
  
  
  CONCLUSIONS
  Our findings indicate that HOTAIR expression has prognostic value for bladder cancer progression, recurrence, and survival and suggest that HOTAIR plays active roles in modulating the cancer epigenome, becoming an interesting candidate as a target for cancer diagnosis and therapy. The observed HOTAIR regulation by EZH2 and the possibility of modulating EZH2 activity with specific inhibitors open new possible paths to be explored in bladder cancer therapy.
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), Av Complutense 40, 28040 Madrid, Spain ; Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Feber
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), Av Complutense 40, 28040 Madrid, Spain ; Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Dueñas
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), Av Complutense 40, 28040 Madrid, Spain ; Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Segovia
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), Av Complutense 40, 28040 Madrid, Spain ; Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Rubio
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), Av Complutense 40, 28040 Madrid, Spain ; Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Fernandez
authors.affiliation: Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Villacampa
authors.affiliation: Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), Av Complutense 40, 28040 Madrid, Spain ; Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Fernando F
authors.initials: FF
authors.lastname: López-Calderón
authors.affiliation: Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Ma José
authors.initials: MJ
authors.lastname: Gómez-Rodriguez
authors.affiliation: Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain ; Servicio de Anatomía Patológica, Hospital Universitario 12 de Octubre, Instituto de Investigación 12 de Octubre i+12, UCM, Av Cordoba s/n., 28041 Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Rodriguez-Peralto
authors.affiliation: Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: de la Rosa
authors.affiliation: Medical Genomics, UCL Cancer Institute, University College London, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: Molecular Oncology Unit, CIEMAT (ed70A), Av Complutense 40, 28040 Madrid, Spain ; Biomedical Research Institute I+12, University Hospital "12 de Octubre", Av Córdoba s/n., 28041 Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
keywords: ANRIL; Bladder cancer; Epigenetics; HOTAIR; LncRNA; Recurrence