Snyder Eric L, Sandstrom Deborah J, Law Kenneth, Fiore Christopher, Sicinska Ewa, Brito Joseph, Bailey Dyane, Fletcher Jonathan A, Loda Massimo, Rodig Scott J, Dal Cin Paola, Fletcher Christopher D M
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Pathol. 2009 Jul;218(3):292-300. doi: 10.1002/path.2564.
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.
c-Jun及其上游激酶的基因组扩增被认为是高分化脂肪肉瘤向去分化脂肪肉瘤进展的一种机制。为了进一步明确c-Jun在脂肪肉瘤进展中的作用，我们对一系列脂肪肉瘤（n = 81）进行了c-Jun及其激活激酶ASK1的免疫组织化学检测。我们将结果与荧光原位杂交检测c-Jun扩增情况进行关联分析。我们还从具有c-Jun扩增的去分化脂肪肉瘤中获得了新的细胞系。c-Jun蛋白在大多数去分化脂肪肉瘤（91%）及其高分化成分（59%）中表达，但仅在少数纯高分化脂肪肉瘤（27%）中表达。当c-Jun在去分化脂肪肉瘤中扩增时，它与扩增的MDM2在环状和巨大标记染色体上相间分布。MDM2扩增是脂肪肉瘤发生过程中最早出现的事件之一，这些结果表明c-Jun在肿瘤演变过程中也在相似时间发生了扩增。此外，在c-Jun扩增的脂肪肉瘤细胞中针对c-Jun的短发夹RNA（shRNA）可在体外减少细胞数量，并在体内抑制肿瘤形成，而对脂肪肉瘤细胞的分化状态没有明显影响。因此，c-Jun扩增在脂肪肉瘤中具有致癌作用，但并不总是足以抑制脂肪细胞分化。
