title: Long Noncoding RNA MALAT1 Promotes Hepatocellular Carcinoma Development by SRSF1 Upregulation and mTOR Activation.
abstract: Several long noncoding RNAs (lncRNA) are abrogated in cancer but their precise contributions to oncogenesis are still emerging. Here we report that the lncRNA MALAT1 is upregulated in hepatocellular carcinoma and acts as a proto-oncogene through Wnt pathway activation and induction of the oncogenic splicing factor SRSF1. Induction of SRSF1 by MALAT1 modulates SRSF1 splicing targets, enhancing the production of antiapoptotic splicing isoforms and activating the mTOR pathway by modulating the alternative splicing of S6K1. Inhibition of SRSF1 expression or mTOR activity abolishes the oncogenic properties of MALAT1, suggesting that SRSF1 induction and mTOR activation are essential for MALAT1-induced transformation. Our results reveal a mechanism by which lncRNA MALAT1 acts as a proto-oncogene in hepatocellular carcinoma, modulating oncogenic alternative splicing through SRSF1 upregulation.Cancer Res; 77(5); 1155-67. ©2016 AACR.
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Pushkar
authors.initials: P
authors.lastname: Malakar
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Shilo
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Mogilevsky
authors.affiliation: Department of Immunology and Cancer Research, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Stein
authors.affiliation: Department of Immunology and Cancer Research, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.affiliation: Bioinformatics unit, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Nevo
authors.affiliation: Bioinformatics unit, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Hadar
authors.initials: H
authors.lastname: Benyamini
authors.affiliation: Bioinformatics unit, the Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel.
authors.forename: Sharona
authors.initials: S
authors.lastname: Elgavish
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zong
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois.
authors.forename: Kannanganattu V
authors.initials: KV
authors.lastname: Prasanth
authors.affiliation: Department of Biochemistry and Molecular Biology, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel. rotemka@ekmd.huji.ac.il.
authors.forename: Rotem
authors.initials: R
authors.lastname: Karni
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D000090063:Proto-Oncogene Mas; D062085:RNA, Long Noncoding / Q000235:genetics*; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014162:Transfection; D015854:Up-Regulation
chemical_list: C557041:MALAT1 long non-coding RNA, human; C000715470:MAS1 protein, human; C557040:Malat1 long non-coding RNA, mouse; D000090063:Proto-Oncogene Mas; D062085:RNA, Long Noncoding; C000595779:SRSF1 protein, human; C494908:Srsf1 protein, mouse; D000068103:Serine-Arginine Splicing Factors; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases