title: TLS-CHOP represses miR-486 expression, inducing upregulation of a metastasis regulator PAI-1 in human myxoid liposarcoma.
abstract: Myxoid liposarcomas (MLSs) are characterized by t(12;16)(q13;p11) translocation and expression of TLS-CHOP chimeric oncoprotein. However, the molecular functions of TLS-CHOP have not been fully understood. On the other hand, microRNAs (miRNAs) comprise an abundant class of endogenous small non-coding RNAs that negatively regulate the expression of their target genes, and are involved in many biological processes. It is now evident that dysregulation of miRNAs is an important step in the development of many cancers. To our knowledge, however, there have been no reports of the miRNAs involved in MLS tumorigenesis and development. In this study, we have found that miR-486 expression was repressed in TLS-CHOP-expressed NIH3T3 fibroblasts and MLS tissues, and exogenous overexpression of miR-486 repressed growth of MLS cells. Thus, downregulation of miR-486 may be an important process for MLS. In addition, we have identified plasminogen activator inhibitor-1 (PAI-1) as a novel target gene of miR-486. PAI-1 is a unique type of serine protease inhibitor and is known to be one of the key regulators of tumor invasion and metastasis. Furthermore, knockdown of PAI-1 by a specific small interfering RNA (siRNA) inhibited growth of MLS cells, suggesting that increased expression of PAI-1 by miR-486 repression is critical for survival of MLS cells. Collectively, these results suggest a novel essential molecular mechanism that TLS-CHOP activates PAI-1 expression by repression of miR-486 expression in MLS tumorigenesis and development.
authors.affiliation: Department of Molecular Pathology, Tokyo Medical University, Tokyo 160-8402, Japan.
authors.forename: Nariso
authors.initials: N
authors.lastname: Borjigin
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ohno
authors.forename: Weihong
authors.initials: W
authors.lastname: Wu
authors.forename: Masami
authors.initials: M
authors.lastname: Tanaka
authors.forename: Rieko
authors.initials: R
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Takanashi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Oikawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Goto
authors.forename: Toru
authors.initials: T
authors.lastname: Motoi
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kosaka
authors.forename: Kengo
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques; D006801:Humans; D018208:Liposarcoma, Myxoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C560945:MIRN486 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D017395:Plasminogen Activator Inhibitor 1; D034702:RNA-Binding Protein FUS; C051321:SERPINE1 protein, human; C106030:TLS-CHOP fusion protein, human; D051742:Transcription Factor CHOP