title: SS18-SSX-regulated miR-17 promotes tumor growth of synovial sarcoma by inhibiting p21WAF1/CIP1.
abstract: MicroRNA (miRNA) can function as tumor suppressors or oncogenes, and also as potential specific cancer biomarkers; however, there are few published studies on miRNA in synovial sarcomas, and their function remains unclear. We transfected the OncomiR miRNA Precursor Virus Library into synovial sarcoma Fuji cells followed by a colony formation assay to identify miRNAs to confer an aggressive tumorigenicity, and identified miR-17-5p from the large colonies. MiR-17 was found to be induced by a chimeric oncoprotein SS18-SSX specific for synovial sarcoma, and all examined cases of human synovial sarcoma expressed miR-17, even at high levels in several cases. Overexpression of miR-17 in synovial sarcoma cells, Fuji and HS-SYII, increased colony forming ability in addition to cell growth, but not cell motility and invasion. Tumor volume formed in mice in vivo was significantly increased by miR-17 overexpression with a marked increase of MIB-1 index. According to PicTar and Miranda algorithms, which predicted CDKN1A (p21) as a putative target of miR-17, a luciferase assay was performed and revealed that miR-17 directly targets the 3'-UTR of p21 mRNA. Indeed, p21 protein level was remarkably decreased by miR-17 overexpression in a p53-independent manner. It is noteworthy that miR-17 succeeded in suppressing doxorubicin-evoked higher expression of p21 and conferred the drug resistance. Meanwhile, introduction of anti-miR-17 in Fuji and HS-SYII cells significantly decreased cell growth, consistent with rescued expression of p21. Taken together, miR-17 promotes the tumor growth of synovial sarcomas by post-transcriptional suppression of p21, which may be amenable to innovative therapeutic targeting in synovial sarcoma.
authors.affiliation: Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Orthopaedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Minami
authors.forename: Shinji
authors.initials: S
authors.lastname: Kohsaka
authors.forename: Masumi
authors.initials: M
authors.lastname: Tsuda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yachi
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Hatori
authors.forename: Mishie
authors.initials: M
authors.lastname: Tanino
authors.forename: Taichi
authors.initials: T
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishihara
authors.forename: Akio
authors.initials: A
authors.lastname: Minami
authors.forename: Norimasa
authors.initials: N
authors.lastname: Iwasaki
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D034622:RNA Interference; D013584:Sarcoma, Synovial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D020413:3' Untranslated Regions; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; C587877:SS18-SSX1 fusion protein; C116512:SYT-SSX fusion protein
keywords: Cyclin-dependent kinase inhibitor p21; SS18-SSX fusion protein; drug resistance; hsa-mir-17 microRNA; synovial sarcoma