TY - JOUR
T1 - Long non-coding RNA containing ultraconserved genomic region 8 promotes bladder cancer tumorigenesis
AU - Olivieri, Michele
AU - Ferro, Matteo
AU - Terreri, Sara
AU - Durso, Montano
AU - Romanelli, Alessandra
AU - Avitabile, Concetta
AU - De Cobelli, Ottavio
AU - Messere, Anna
AU - Bruzzese, Dario
AU - Vannini, Ivan
AU - Marinelli, Luciana
AU - Novellino, Ettore
AU - Zhang, Wei
AU - Incoronato, Mariarosaria
AU - Ilardi, Gennaro
AU - Staibano, Stefania
AU - Marra, Laura
AU - Franco, Renato
AU - Perdonà, Sisto
AU - Terracciano, Daniela
AU - Czerniak, Bogdan
AU - Liguori, Giovanna L.
AU - Colonna, Vincenza
AU - Fabbri, Muller
AU - Febbraio, Ferdinando
AU - Calin, George A.
AU - Cimmino, Amelia
PY - 2016/4/12
Y1 - 2016/4/12
N2 - 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.
AB - 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.
KW - Bladder cancer
KW - CASZ1
KW - MMP9
KW - MicroRNA
KW - T-UCR
UR - http://www.scopus.com/inward/record.url?scp=84964700497&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964700497&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7833
DO - 10.18632/oncotarget.7833
M3 - Article
C2 - 26943042
AN - SCOPUS:84964700497
SN - 1949-2553
VL - 7
SP - 20636
EP - 20654
JO - Oncotarget
JF - Oncotarget
IS - 15
ER -