Small RNA sequencing and functional characterization reveals microrna-143 tumor suppressor activity in liposarcoma Journal Article


Authors: Ugras, S.; Brill, E.; Jacobsen, A.; Hafner, M.; Socci, N. D.; Decarolis, P. L.; Khanin, R.; O'Connor, R.; Mihailovic, A.; Taylor, B. S.; Sheridan, R.; Gimble, J. M.; Viale, A.; Crago, A.; Antonescu, C. R.; Sander, C.; Tuschl, T.; Singer, S.
Article Title: Small RNA sequencing and functional characterization reveals microrna-143 tumor suppressor activity in liposarcoma
Abstract: Liposarcoma remains the most common mesenchymal cancer, with a mortality rate of 60% among patients with this disease. To address the present lack of therapeutic options, we embarked upon a study of microRNA (miRNA) expression alterations associated with liposarcomagenesis with the goal of exploiting differentially expressed miRNAs and the gene products they regulate as potential therapeutic targets. MicroRNA expression was profiled in samples of normal adipose tissue, well-differentiated liposarcoma, and dedifferentiated liposarcoma by both deep sequencing of small RNA libraries and hybridization-based Agilent microarrays. The expression profiles discriminated liposarcoma from normal adipose tissue and well differentiated from dedifferentiated disease. We defined over 40 miRNAs that were dysregulated in dedifferentiated liposarcomas in both the sequencing and the microarray analysis. The upregulated miRNAs included two cancer-associated species (miR-21 and miR-26a), and the downregulated miRNAs included two species that were highly abundant in adipose tissue (miR-143 and miR-145). Restoring miR-143 expression in dedifferentiated liposarcoma cells inhibited proliferation, induced apoptosis, and decreased expression of BCL2, topoisomerase 2A, protein regulator of cytokinesis 1 (PRC1), and polo-like kinase 1 (PLK1). The downregulation of PRC1 and its docking partner PLK1 suggests that miR-143 inhibits cytokinesis in these cells. In support of this idea, treatment with a PLK1 inhibitor potently induced G2-M growth arrest and apoptosis in liposarcoma cells. Taken together, our findings suggest that miR-143 re-expression vectors or selective agents directed at miR-143 or its targets may have therapeutic value in dedifferentiated liposarcoma. ©2011 AACR.
Keywords: controlled study; human tissue; protein expression; unclassified drug; human cell; cell proliferation; protein bcl 2; apoptosis; microrna; gene expression; gene expression profiling; antineoplastic activity; carcinogenesis; cancer inhibition; microarray analysis; polo like kinase 1; cancer cell; down regulation; upregulation; dna topoisomerase (atp hydrolysing); liposarcoma; adipose tissue; cytokinesis; regulator protein; rna sequence; cell dedifferentiation; 4 (8 cyclopentyl 7 ethyl 5,6,7,8 tetrahydro 5 methyl 6 oxo 2 pteridinylamino) 3 methoxy n (1 methyl 4 piperidinyl)benzamide; protein regulator of cytokinesis 1; rna hybridization
Journal Title: Cancer Research
Volume: 71
Issue: 17
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2011-09-01
Start Page: 5659
End Page: 5669
Language: English
DOI: 10.1158/0008-5472.can-11-0890
PROVIDER: scopus
PMCID: PMC3165140
PUBMED: 21693658
DOI/URL:
Notes: --- - "Export Date: 3 October 2011" - "CODEN: CNREA" - "Source: Scopus"
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MSK Authors
  1. Cristina R Antonescu
    903 Antonescu
  2. Elliott R Brill
    8 Brill
  3. Aimee Marie Crago
    106 Crago
  4. Samuel Singer
    337 Singer
  5. Agnes Viale
    246 Viale
  6. Nicholas D Socci
    266 Socci
  7. Raya Khanin
    46 Khanin
  8. Chris Sander
    210 Sander
  9. Stacy Katherine Ugras
    14 Ugras
  10. Barry Stephen Taylor
    238 Taylor