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c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas.

Authors
  • Sioletic, Stefano1
  • Czaplinski, Jeffrey
  • Hu, Lan
  • Fletcher, Jonathan A
  • Fletcher, Christopher D M
  • Wagner, Andrew J
  • Loda, Massimo
  • Demetri, George D
  • Sicinska, Ewa T
  • Snyder, Eric L
  • 1 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
Type
Published Article
Journal
The Journal of Pathology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2014
Volume
234
Issue
2
Pages
190–202
Identifiers
DOI: 10.1002/path.4379
PMID: 24852265
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Genomic amplification of the c-Jun proto-oncogene has been identified in ∼30% of dedifferentiated liposarcomas (DDLPS), but the functional contribution of c-Jun to the progression of DDLPS remains poorly understood. In previous work we showed that knock-down of c-Jun by RNA interference impaired the in vitro proliferation and in vivo growth of a DDLPS cell line (LP6) with genomic amplification of the c-Jun locus. Here, we used gene expression analysis and functional studies in a broad panel of cell lines to further define the role of c-Jun in DDLPS and other soft tissue sarcomas. We show that c-Jun knock-down impairs transition through the G1 phase of the cell cycle in multiple DDLPS cell lines. We also found that high levels of c-Jun expression are both necessary and sufficient to promote DDLPS cell migration and invasion in vitro. Our data suggest that high levels of c-Jun enhance motility in part by driving the expression of ENPP2/Autotaxin. c-Jun over-expression has minimal effects on in vitro proliferation but substantially enhances the in vivo growth of weakly tumourigenic DDLPS cell lines. Finally, we provide evidence that c-Jun genomic amplification and over-expression may have similar functional consequences in other types of soft tissue sarcoma. Our data suggest a model in which relatively low levels of c-Jun are sufficient for in vitro proliferation, but high levels of c-Jun enhance invasiveness and capacity for in vivo tumour growth. These observations provide an explanation for the selective advantage provided by c-Jun genomic amplification in vivo and suggest that sarcomas with elevated c-Jun levels are likely to have a particularly high malignant potential. Data from exon array and RNA-Seq experiments have been deposited in the GEO database (Accession No. GSE57531). Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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