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Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs.

ABSTRACT: The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis. Their mechanisms of action and the factors regulating their expression in cancers are poorly understood. Here we show that high expression of uc.339 correlates with lower survival in 210 non-small cell lung cancer (NSCLC) patients. We provide evidence from cell lines and primary samples that TP53 directly regulates uc.339. We find that transcribed uc.339 is upregulated in archival NSCLC samples, functioning as a decoy RNA for miR-339-3p, -663b-3p, and -95-5p. As a result, Cyclin E2, a direct target of all these microRNAs is upregulated, promoting cancer growth and migration. Finally, we find that modulation of uc.339 affects microRNA expression. However, overexpression or downregulation of these microRNAs causes no significant variations in uc.339 levels, suggesting a type of interaction for uc.339 that we call "entrapping". Our results support a key role for uc.339 in lung cancer.

SUBMITTER: Vannini I

PROVIDER: S-EPMC5703849 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs.

Vannini Ivan I Wise Petra M PM Challagundla Kishore B KB Plousiou Meropi M Raffini Mirco M Bandini Erika E Fanini Francesca F Paliaga Giorgia G Crawford Melissa M Ferracin Manuela M Ivan Cristina C Fabris Linda L Davuluri Ramana V RV Guo Zhiyi Z Cortez Maria Angelica MA Zhang Xinna X Chen Lu L Zhang Shuxing S Fernandez-Cymering Cecilia C Han Leng L Carloni Silvia S Salvi Samanta S Ling Hui H Murtadha Mariam M Neviani Paolo P Gitlitz Barbara J BJ Laird-Offringa Ite A IA Nana-Sinkam Patrick P Negrini Massimo M Liang Han H Amadori Dino D Cimmino Amelia A Calin George A GA Calin George A GA Fabbri Muller M

Nature communications 20171127 1

The transcribed ultraconserved regions (T-UCRs) encode long non-coding RNAs implicated in human carcinogenesis. Their mechanisms of action and the factors regulating their expression in cancers are poorly understood. Here we show that high expression of uc.339 correlates with lower survival in 210 non-small cell lung cancer (NSCLC) patients. We provide evidence from cell lines and primary samples that TP53 directly regulates uc.339. We find that transcribed uc.339 is upregulated in archival NSCL ...[more]

PMID: 29180617

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Project description: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.

Dataset Information

Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs.

Publications

Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs.

Similar Datasets

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