c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas.
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).
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Ludwig Center at Dana-Farber/Harvard Cancer Center, Boston, MA, USA.
Stefano
S
Sioletic
Jeffrey
J
Czaplinski
Lan
L
Hu
Jonathan A
JA
Fletcher
Christopher D M
CD
Fletcher
Andrew J
AJ
Wagner
Massimo
M
Loda
George D
GD
Demetri
Ewa T
ET
Sicinska
Eric L
EL
Snyder
D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics*; D006801:Humans; D008080:Liposarcoma / Q000378:metabolism*; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000099189:Lysophospholipase D
D010727:Phosphoric Diester Hydrolases; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D000099189:Lysophospholipase D; C000715470:MAS1 protein, human
ENPP2; autotaxin; c-Jun; liposarcoma; soft tissue sarcoma