Characterization of Three Novel H3F3A-mutated Giant Cell Tumor Cell Lines and Targeting of Their Wee1 Pathway

Autor:	Kevin Mellert, Christoph Lübbehüsen, Ralf Marienfeld, Julian Lüke, Peter Möller, Thomas F. E. Barth, Markus Schultheiss, Alexandra von Baer, Carolin Seeling
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine Adult Male Osteolysis Stromal cell Adolescent Population lcsh:Medicine Bone Neoplasms Cell Cycle Proteins Biology Histones 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans education lcsh:Science Giant Cell Tumor of Bone Cyclin-dependent kinase 1 education.field_of_study Multidisciplinary lcsh:R Protein-Tyrosine Kinases medicine.disease Neoplasm Proteins 030104 developmental biology Cell culture Giant cell Mutation Cancer research Female lcsh:Q Sarcoma 030217 neurology & neurosurgery Giant-cell tumor of bone Signal Transduction
Zdroj:	Scientific Reports, Vol 9, Iss 1, Pp 1-10 (2019)
ISSN:	2045-2322
DOI:	10.1038/s41598-019-42611-1
Popis:	The giant cell tumor of bone (GCTB) is a locally aggressive primary bone tumor that is composed of mononuclear stroma cells, scattered macrophages, and multinucleated osteoclast-like giant cells which cause pathologic osteolysis. The stroma cells represent the neoplastic population of the tumor and are characterized by the H3F3A mutation G34W. This point mutation is regarded as the driver mutation of GCTB. We have established three new stable H3F3A mutated GCTB cell lines: U-GCT1, U-GCT2, and U-GCT3M. MK-1775 is a Wee1-kinase inhibitor which has been used for blocking of sarcoma growth. In the cell lines we detected Wee1, Cdk1, Cyclin B1, H3K36me3, and Rrm2 as members of the Wee1 pathway. We analyzed the effect of MK-1775 and gemcitabine, alone and in combination, on the growth of the cell lines. The cell lines showed a significant reduction in cell proliferation when treated with MK-1775 or gemcitabine. The combination of both agents led to a further significant reduction in cell proliferation compared to the single agents. Immunohistochemical analysis of 13 GCTB samples revealed that Wee1 and downstream-relevant members are present in GCTB tissue samples. Overall, our work offers valuable new tools for GCTB studies and presents a description of novel biomarkers and molecular targeting strategies.
Databáze:	OpenAIRE
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