Research Papers:

Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis

Michele Olivieri, Matteo Ferro, Sara Terreri, Montano Durso, Alessandra Romanelli, Concetta Avitabile, Ottavio De Cobelli, Anna Messere, Dario Bruzzese, Ivan Vannini, Luciana Marinelli, Ettore Novellino, Wei Zhang, Mariarosaria Incoronato, Gennaro Ilardi, Stefania Staibano, Laura Marra, Renato Franco, Sisto Perdonà, Daniela Terracciano, Bogdan Czerniak, Giovanna L. Liguori, Vincenza Colonna, Muller Fabbri, Ferdinando Febbraio, George A. Calin and Amelia Cimmino _

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Oncotarget. 2016; 7:20636-20654. https://doi.org/10.18632/oncotarget.7833

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Michele Olivieri1,*, Matteo Ferro2,*, Sara Terreri1,*, Montano Durso1,3, Alessandra Romanelli4, Concetta Avitabile4, Ottavio De Cobelli2, Anna Messere5, Dario Bruzzese6, Ivan Vannini7, Luciana Marinelli4, Ettore Novellino4, Wei Zhang8, Mariarosaria Incoronato9, Gennaro Ilardi10, Stefania Staibano10, Laura Marra11, Renato Franco12, Sisto Perdonà11, Daniela Terracciano13, Bogdan Czerniak8, Giovanna L. Liguori1, Vincenza Colonna1, Muller Fabbri14, Ferdinando Febbraio15, George A. Calin16,*, Amelia Cimmino1,*

1Institute of Genetics and Biophysics “A. Buzzati Traverso”, National Research Council (CNR), Naples, Italy

2Division of Urology, European Institute of Oncology, Milan, Italy

3Bio-Ker S.r.l. MultiMedica S.p.A. Naples, Italy

4Department of Pharmacy, University of Naples “Federico II”, Naples, Italy

5Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples, Naples, Italy

6Department of Public Health, University of Naples “Federico II”, Naples, Italy

7Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l. IRCCS, Gene Therapy Unit, Meldola, Italy

8Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

9Fondazione IRCCS SDN, Naples, Italy

10Department of Advanced Biomedical Sciences, University of Naples “Federico II”, Naples, Italy

11Division of Urology, IRCS National Tumor Institute, Naples, Italy

12Department of Physical and Mental Health and Preventive Medicine, Section of Pathology, Second University of Naples, Naples, Italy

13Department of Translational Medical Sciences, University of Naples “Federico II”, Naples, Italy

14Department of Pediatrics and Molecular Microbiology & Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Children’s Center for Cancer and Blood Diseases and The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, USA

15Institute of Protein Biochemistry, National Research Council (CNR), Naples, Italy

16Department of Experimental Therapeutics and The Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

*These authors contributed equally to this work

Correspondence to:

Amelia Cimmino, e-mail: [email protected]

Ferdinando Febbraio, e-mail: [email protected]

George A. Calin, e-mail: [email protected]

Keywords: microRNA, T-UCR, bladder cancer, MMP9, CASZ1

Received: January 22, 2016     Accepted: February 03, 2016     Published: March 01, 2016


Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies.

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