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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.
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1 Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l., IRCCS, Gene Therapy Unit, Meldola (FC), Italy
2 Departments 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
3 Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
4 Department of Internal Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, USA
5 Department of Experimental, Diagnostic and Specialty Medicine—DIMES, University of Bologna, Bologna, Italy
6 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
7 The Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
8 Departments of Preventive Medicine and Neurological Surgery, Northwestern University-Feinberg School of Medicine, Chicago, IL, USA
9 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
10 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
11 The Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
12 Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
13 Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH, USA
14 Department of Biochemistry and Molecular Biology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
15 Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l., IRCCS, Biosciences Laboratory Unit, Meldola (FC), Italy
16 Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
17 Departments of Surgery and Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
18 Division of Pulmonary Diseases and Critical Care Medicine, Virginia Commonwealth University, Richmond, VA, USA
19 Department of Morphology, Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy
20 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
21 Department of Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l., IRCCS, Meldola (FC), Italy
22 Institute of Genetics and Biophysics, National Research Council, Naples, Italy