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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) are segments of the human genome located in both intragenic and intergenic regions that are highly conserved in orthologous regions of the human, rat, and mouse genomes. Their transcriptional products, called T-UCRs, compose a new category of long noncoding RNA (lncRNAs). Most importantly, recent data suggests that T-UCRs are altered at the transcriptional level in human tumorigenesis and the aberrant T-UCRs expression profiles can be used to differentiate human cancer types. MicroRNAs and other types of non-codingRNAs have been shown to greatly contribute at biological function of cancer and are increasingly being used to help prognosticate patients with bladder cancer, this is not yet the case for T-UCRs. The presence and the roles for T-UCRs across different species is largely unknown rendering their investigation particularly important in our understanding the biology of cancer. Using genome-wide profiling, we identified 293 T-UCRs that were dysregulated in bladder tumor (n = 24) but not normal bladder tissues (n = 17) samples. The greatest change in expression was for the ultraconserved element 8 (uc.8+), whose expression significantly increased (6.7 fold; P = 0.001) in bladder cancer tissues. Dysregulated expression was validated for several T-UCRs in 60 patients and 16 healthy donors. We found that T-UCR 8+ acts as a natural decoy RNA for miR-596 in patients and bladder cancer cells. As a result, expression of matrix metallopeptidase 9, a direct target of this microRNA, was upregulated, thereby promoting cancer cell growth, migration, and invasion. We also observed that mir-596 mediated a network of interactions among uc.8+, uc.339+, uc.195+, and uc.388+, which appeared to be dysregulated in bladder tumors. Transcribed ultraconserved ncRNAs provide an evolutionarily-conserved regulatory layer that modulates miRNA levels, and opens up the possibility for the development of useful markers for diagnosis and prognosis, as well as for the 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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