c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programme.
Genomic amplification of c-Jun and its upstream kinases have been implicated as a mechanism of progression from well-differentiated to dedifferentiated liposarcoma. To further define the role of c-Jun in liposarcoma progression, we performed immunohistochemistry for c-Jun and its activating kinase ASK1 on a series of liposarcomas (n = 81). We correlated the results with fluorescence in situ hybridization to detect c-Jun amplification. We also derived new cell lines from dedifferentiated liposarcomas with c-Jun amplification. c-Jun protein is expressed in the majority of dedifferentiated liposarcomas (91%) and their well-differentiated components (59%), but only in the minority of pure well-differentiated liposarcomas (27%). When c-Jun is amplified in dedifferentiated liposarcoma, it is interspersed with amplified MDM2 on ring and giant marker chromosomes. MDM2 amplification is one of the earliest events in liposarcoma development, and these results suggest that c-Jun was amplified at a similar time in the evolution of the tumour. In addition, shRNA to c-Jun in c-Jun-amplified liposarcoma cells reduces cell number in vitro and inhibits tumour formation in vivo without an observable effect on the differentiation state of the liposarcoma cells. Thus, c-Jun amplification is oncogenic in liposarcomas but not always sufficient for inhibition of adipocytic differentiation.
Snyder
Eric L
EL
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sandstrom
Deborah J
DJ
Law
Kenneth
K
Fiore
Christopher
C
Sicinska
Ewa
E
Brito
Joseph
J
Bailey
Dyane
D
Fletcher
Jonathan A
JA
Loda
Massimo
M
Rodig
Scott J
SJ
Dal Cin
Paola
P
Fletcher
Christopher D M
CD
D017667:Adipocytes / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D018450:Disease Progression; D005784:Gene Amplification; D016758:Genes, jun; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008080:Liposarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*
D016755:Proto-Oncogene Proteins c-jun; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human