Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs

Ivan Vannini, Petra M. Wise, Kishore B. Challagundla, Meropi Plousiou, Mirco Raffini, Erika Bandini, Francesca Fanini, Giorgia Paliaga, Melissa Crawford, Manuela Ferracin, Cristina Ivan, Linda Fabris, Ramana V. Davuluri, Zhiyi Guo, Maria Angelica Cortez, Xinna Zhang, Lu Chen, Shuxing Zhang, Cecilia Fernandez-Cymering, Leng Han, Silvia Carloni, Samanta Salvi, Hui Ling, Mariam Murtadha, Paolo Neviani, Barbara J. Gitlitz, Ite A. Laird-Offringa, Patrick Nana-Sinkam, Massimo Negrini, Han Liang, Dino Amadori, Amelia Cimmino, George A. Calin () and Muller Fabbri ()
Additional contact information
Ivan Vannini: IRCCS, Gene Therapy Unit
Petra M. Wise: 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
Kishore B. Challagundla: University of Nebraska Medical Center
Meropi Plousiou: IRCCS, Gene Therapy Unit
Mirco Raffini: IRCCS, Gene Therapy Unit
Erika Bandini: IRCCS, Gene Therapy Unit
Francesca Fanini: IRCCS, Gene Therapy Unit
Giorgia Paliaga: IRCCS, Gene Therapy Unit
Melissa Crawford: The Ohio State University
Manuela Ferracin: Diagnostic and Specialty Medicine—DIMES, University of Bologna
Cristina Ivan: The University of Texas MD Anderson Cancer Center
Linda Fabris: The University of Texas MD Anderson Cancer Center
Ramana V. Davuluri: Northwestern University-Feinberg School of Medicine
Zhiyi Guo: The University of Texas MD Anderson Cancer Center
Maria Angelica Cortez: The University of Texas MD Anderson Cancer Center
Xinna Zhang: The University of Texas MD Anderson Cancer Center
Lu Chen: The University of Texas MD Anderson Cancer Center
Shuxing Zhang: The University of Texas MD Anderson Cancer Center
Cecilia Fernandez-Cymering: Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University
Leng Han: McGovern Medical School, The University of Texas Health Science Center at Houston
Silvia Carloni: IRCCS, Biosciences Laboratory Unit
Samanta Salvi: IRCCS, Biosciences Laboratory Unit
Hui Ling: The University of Texas MD Anderson Cancer Center
Mariam Murtadha: 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
Paolo Neviani: 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
Barbara J. Gitlitz: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
Ite A. Laird-Offringa: Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California
Patrick Nana-Sinkam: Virginia Commonwealth University
Massimo Negrini: Surgery and Experimental Medicine and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara
Han Liang: The University of Texas MD Anderson Cancer Center
Dino Amadori: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) S.r.l., IRCCS
Amelia Cimmino: National Research Council
George A. Calin: The University of Texas MD Anderson Cancer Center
Muller Fabbri: 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

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01562-9

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