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Abstract

Soft tissue sarcomas are a rare group of highly aggressive, histologically and genetically heterogeneous malignant tumors of mesenchymal origin. Liposarcomas are the most common type of sarcomas and are classified into the three types well-differentiated / dedifferentiated liposarcomas, pleomorphic liposarcomas and myxoid liposarcomas (MLS). MLS are characterized by a t(12;16)(q13;p11) translocation resulting in a FUS-DDIT3 fusion protein causing a block of differentiation during adipogenesis and malignant transformation. SOX11 is a neuronal transcription factor which is expressed during embryonic development of central and peripheral nervous system. In adult tissues SOX11 is rarely expressed. SOX11 expression is elevated in a variety of tumors but seems to exert different functions in tumorigenesis. Prior to this study a genome-wide expression profile of primary MLS samples identified SOX11 as the significant most upregulated gene in comparison to non-neoplastic adipose tissue. Additionally, SOX11 target genes in MLS were identified. The overexpression of SOX11 in the SOX11-negative MLS cell line MLS-1765 decreased migration, clonogenicity, and viability. In addition, the reduced cell growth is caused by decreased proliferation. However, overexpression of SOX11 had no influence on apoptosis and necrosis and on the phosphorylation profile of MLS-1765 cells. Also, SOX11 increased the sensitivity of MLS-1765 cells against treatment with the chemotherapeutic drugs dasatinib and trabectedin, but not against the standard first line treatment doxorubicin. The potential target genes LHX2, TMSB15A, CD24, NNAT, THEM6, TUBB2B und SOX11 were validated by qPCR. Positive correlation of gene expression with SOX11 in primary MLS and non-neoplastic adipose tissue and results from dual-luciferase reporter assays revealed that CD24 and LHX2 are putative direct target genes of SOX11. The treatment of T778 cells with histone deacetylase inhibitors indicated that the SOX11 expression in liposarcomas may be regulated via histone modifications. Sequencing of the chromosomal SOX11 gene locus identified a somatic heterozygous mutation (c.248T>A; SOX11T248A) in the tumor of a patient with MLS. According to in silico analyses the SOX11T248A mutation significantly affects folding of the HMG-box domain leading to a loss of DNA binding. Stable overexpression of SOX11T248A in MLS-1765 cells showed reduced ability to activate the downstream transcription of the seven SOX11 target genes and impaired the SOX11-mediated phenotypes proliferation and chemosensitivity against trabectedin. Taken together, this study obtained first evidence for a tumor suppressive role of SOX11, validated CD24 and LHX2 as potential SOX11 target genes and discovered a SOX11 loss-of-function mutation.