title: Dysregulation of a family of short noncoding RNAs, tsRNAs, in human cancer.
abstract: Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and transgenic mouse studies indicate that activation of the T-cell leukemia/lymphoma 1 (TCL1) oncogene is a contributing event in the pathogenesis of the aggressive form of this disease. While studying the regulation of TCL1 expression, we identified the microRNA cluster miR-4521/3676 and discovered that these two microRNAs are associated with tRNA sequences and that this region can produce two small RNAs, members of a recently identified class of small noncoding RNAs, tRNA-derived small RNAs (tsRNAs). We further proved that miR-3676 and miR-4521 are tsRNAs using Northern blot analysis. We found that, like ts-3676, ts-4521 is down-regulated and mutated in CLL. Analysis of lung cancer samples revealed that both ts-3676 and ts-4521 are down-regulated and mutated in patient tumor samples. Because tsRNAs are similar in nature to piRNAs [P-element-induced wimpy testis (Piwi)-interacting small RNAs], we investigated whether ts-3676 and ts-4521 can interact with Piwi proteins and found these two tsRNAs in complexes containing Piwi-like protein 2 (PIWIL2). To determine whether other tsRNAs are involved in cancer, we generated a custom microarray chip containing 120 tsRNAs 16 bp or more in size. Microarray hybridization experiments revealed tsRNA signatures in CLL and lung cancer, indicating that, like microRNAs, tsRNAs may have an oncogenic and/or tumor-suppressor function in hematopoietic malignancies and solid tumors. Thus, our results show that tsRNAs are dysregulated in human cancer.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; pekarsky.yuri@osumc.edu carlo.croce@osumc.edu.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pekarsky
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Veronica
authors.initials: V
authors.lastname: Balatti
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Alexey
authors.initials: A
authors.lastname: Palamarchuk
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Lara
authors.initials: L
authors.lastname: Rizzotto
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Dario
authors.initials: D
authors.lastname: Veneziano
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nigita
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Laura Z
authors.initials: LZ
authors.lastname: Rassenti
authors.affiliation: New York University Langone Medical Center, New York, NY 10016;
authors.forename: Harvey I
authors.initials: HI
authors.lastname: Pass
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, CA 92093;
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: MD Anderson Cancer Center, Houston, TX 77030.
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210; Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; pekarsky.yuri@osumc.edu carlo.croce@osumc.edu.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics*; D058727:RNA, Small Untranslated / Q000235:genetics*; D012343:RNA, Transfer / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D012334:RNA, Neoplasm; D058727:RNA, Small Untranslated; D012343:RNA, Transfer
keywords: ts-3676; ts-4521; tsRNAs