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miR-193b-Regulated Signaling Networks Serve as Tumor Suppressors in Liposarcoma and Promote Adipogenesis in Adipose-Derived Stem Cells.
Mazzu, Ying Z; Hu, Yulan; Soni, Rajesh K; Mojica, Kelly M; Qin, Li-Xuan; Agius, Phaedra; Waxman, Zachary M; Mihailovic, Aleksandra; Socci, Nicholas D; Hendrickson, Ronald C; Tuschl, Thomas; Singer, Samuel.
Affiliation
  • Mazzu YZ; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hu Y; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Soni RK; Microchemistry and Proteomics Core, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Mojica KM; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Qin LX; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Agius P; Bioinformatics Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Waxman ZM; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Mihailovic A; Laboratory of RNA Molecular Biology, The Rockefeller University, New York, New York.
  • Socci ND; Bioinformatics Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Hendrickson RC; Microchemistry and Proteomics Core, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Tuschl T; Laboratory of RNA Molecular Biology, The Rockefeller University, New York, New York.
  • Singer S; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. singers@mskcc.org.
Cancer Res ; 77(21): 5728-5740, 2017 11 01.
Article in En | MEDLINE | ID: mdl-28882999
Well-differentiated and dedifferentiated liposarcomas (WDLS/DDLS) account for approximately 13% of all soft tissue sarcoma in adults and cause substantial morbidity or mortality in the majority of patients. In this study, we evaluated the functions of miRNA (miR-193b) in liposarcoma in vitro and in vivo Deep RNA sequencing on 93 WDLS, 145 DDLS, and 12 normal fat samples demonstrated that miR-193b was significantly underexpressed in DDLS compared with normal fat. Reintroduction of miR-193b induced apoptosis in liposarcoma cells and promoted adipogenesis in human adipose-derived stem cells (ASC). Integrative transcriptomic and proteomic analysis of miR-193b-target networks identified novel direct targets, including CRK-like proto-oncogene (CRKL) and focal adhesion kinase (FAK). miR-193b was found to regulate FAK-SRC-CRKL signaling through CRKL and FAK. miR-193b also stimulated reactive oxygen species signaling by targeting the antioxidant methionine sulfoxide reductase A to modulate liposarcoma cell survival and ASC differentiation state. Expression of miR-193b in liposarcoma cells was downregulated by promoter methylation, resulting at least in part from increased expression of the DNA methyltransferase DNMT1 in WDLS/DDLS. In vivo, miR-193b mimetics and FAK inhibitor (PF-562271) each inhibited liposarcoma xenograft growth. In summary, miR-193b not only functions as a tumor suppressor in liposarcoma but also promotes adipogenesis in ASC. Furthermore, this study reveals key tyrosine kinase and DNA methylation pathways in liposarcoma, some with immediate implications for therapeutic exploration. Cancer Res; 77(21); 5728-40. ©2017 AACR.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Stem Cells / Signal Transduction / Gene Expression Regulation, Neoplastic / MicroRNAs / Adipogenesis / Liposarcoma Limits: Animals / Humans Language: En Journal: Cancer Res Year: 2017 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Stem Cells / Signal Transduction / Gene Expression Regulation, Neoplastic / MicroRNAs / Adipogenesis / Liposarcoma Limits: Animals / Humans Language: En Journal: Cancer Res Year: 2017 Document type: Article Country of publication: United States