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Transcribed ultraconserved region 339 promotes carcinogenesis by sequestering tumor suppressor microRNAs

ABSTRACT: The transcribed ultraconserved regions (T-UCRs) are a family of long non-coding RNAs implicated in human carcinogenesis. The mechanism of action of T-UCRs and the factors regulating their expression in human cancers are poorly understood. In this study we show that high expression of uc.339 correlates with lower survival in 204 non-small cell lung cancer (NSCLC) patients. We also show that uc.339 found up-regulated in archival NSCLC samples, functions as a decoy for miR-339-3p, -663-3p and -95-5p. As a result, Cyclin E2, a direct target of these microRNAs is up-regulated, promoting cancer growth and migration. We provide evidence from cell lines and primary samples suggesting that TP53 directly regulates uc.339. Our results support a key role for uc.339 in lung cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70540 | GEO | 2015/07/07

SECONDARY ACCESSION(S): PRJNA288971

REPOSITORIES: GEO

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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.

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Transcribed ultraconserved region 339 promotes carcinogenesis by sequestering tumor suppressor microRNAs

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