miR-193b-regulated signaling networks serve as tumor suppressors in liposarcoma and promote adipogenesis in adipose-derived stem cells Journal Article

Authors: Mazzu, Y. Z.; Hu, Y.; Soni, R. K.; Mojica, K. M.; Qin, L. X.; Agius, P.; Waxman, Z. M.; Mihailovic, A.; Socci, N. D.; Hendrickson, R. C.; Tuschl, T.; Singer, S.
Article Title: miR-193b-regulated signaling networks serve as tumor suppressors in liposarcoma and promote adipogenesis in adipose-derived stem cells
Abstract: 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 American Association for Cancer Research.
Keywords: signal transduction; controlled study; unclassified drug; human cell; promoter region; genetics; nonhuman; mouse; animal; cytology; metabolism; animals; animal tissue; cell survival; apoptosis; microrna; gene expression; gene expression profiling; nuclear protein; animal experiment; animal model; gene function; in vivo study; cell differentiation; in vitro study; tumor xenograft; drug screening; institute for cancer research mouse; pathology; mice, inbred icr; mice, scid; xenograft model antitumor assays; cell line, tumor; proteomics; transcriptomics; dna methylation; stem cell; nuclear proteins; gene expression regulation; tumor suppressor gene; gene expression regulation, neoplastic; sulfonamide; sulfonamides; tumor cell line; reactive oxygen species; reactive oxygen metabolite; adaptor proteins, signal transducing; stem cells; down regulation; micrornas; indoles; indole derivative; focal adhesion kinase; signal transducing adaptor protein; scid mouse; genes, tumor suppressor; dna methyltransferase 1; liposarcoma; adipose tissue; rna sequence; focal adhesion kinase 1; ptk2 protein, human; adipogenesis; procedures; dedifferentiated liposarcoma; adipose derived stem cell; crk like protein; well differentiated liposarcoma; pf 562271; humans; human; priority journal; article; methionine sulfoxide reductase; microrna 193b; mirn193 microrna, human; n-methyl-n-(3-((2-(2-oxo-2,3-dihydro-1h-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; methionine sulfoxide reductases
Journal Title: Cancer Research
Volume: 77
Issue: 21
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2017-11-01
Start Page: 5728
End Page: 5740
Language: English
DOI: 10.1158/0008-5472.can-16-2253
PUBMED: 28882999
PROVIDER: scopus
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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MSK Authors
  1. Li-Xuan Qin
    111 Qin
  2. Samuel Singer
    224 Singer
  3. Rajesh Kumar Soni
    12 Soni
  4. Nicholas D Socci
    182 Socci
  5. Phaedra Agius
    11 Agius
  6. Ying Zhang Mazzu
    4 Mazzu
  7. Yu Lan Hu
    1 Hu
  8. Zachary Waxman
    1 Waxman