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Role of FUS-CHOP in Myxoid Liposarcoma via miR-486/CDK4 Axis
Hao Wu1, Liming Xia2, Haichao Xu1
1Bone and Soft Tissue Sarcoma Department, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, No. 1 Banshan East Road, Gongshu District, Hangzhou, 310022, China.
Abstract:
This study aimed to explore the roles and relationship between FUsed in Sarcoma (FUS)-C/EBP HOmologous Protein (CHOP), microRNA (miR)-486 and cyclin dependent kinase 4 (CDK4) in myxoid liposarcoma, and determined whether FUS-CHOP can regulate proliferation and apoptosis of myxoid liposarcoma cells by regulating miR-486/CDK4 axis. The levels of miR-486, CDK4 and FUS-CHOP in myxoid liposarcoma samples/adjacent normal muscle tissues and myxoid liposarcoma/human adipose-derived stem cell line were evaluated using reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation and apoptosis were performed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and flow cytometry, respectively. Furthermore, the apoptosis-related proteins were determined using Western blot assay. We found that miR-486 was down-regulated, FUS-CHOP and CDK4 were up-regulated in myxoid liposarcoma tissues and myxoid liposarcoma cell lines. Moreover, FUS-CHOP-siRNA distinctly suppressed FUS-CHOP level and increased miR-486 levels in 1955/91 cells. Our results demonstrated that knockdown of FUS-CHOP by siRNA inhibited 1955/91 growth, promoted cell apoptosis and enhanced cleaved Caspase3 protein expression. However, all these data were reversed by miR-486 inhibitor. Similarly, compared to mimic control, miR-486 mimic markedly reduced 1955/91 cells growth, induced cell apoptosis and fortified cleaved Caspase3 level, while these results were abolished by CDK4-plasmid. Collectively, our observations clearly suggested that FUS-CHOP regulated myxoid liposarcoma cell proliferation and apoptosis by the regulation of miR-486/CDK4 axis, indicating the potential use of FUS-CHOP-siRNA as a promising therapy for myxoid liposarcoma.
Insights
FUS-CHOP regulates myxoid liposarcoma cell growth and apoptosis by controlling the miR-486/CDK4 pathway. Targeting FUS-CHOP with siRNA shows therapeutic potential for myxoid liposarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Myxoid liposarcoma is characterized by the Fused in Sarcoma (FUS)-C/EBP Homologous Protein (CHOP) fusion oncogene.
- The roles of microRNA (miR)-486 and cyclin-dependent kinase 4 (CDK4) in this context are not fully understood.
Purpose of the Study:
- To investigate the relationship between FUS-CHOP, miR-486, and CDK4 in myxoid liposarcoma.
- To determine if FUS-CHOP regulates myxoid liposarcoma cell proliferation and apoptosis via the miR-486/CDK4 axis.
Main Methods:
- Quantitative reverse transcription-PCR and Western blotting to assess molecule levels.
- Cell proliferation assays (MTT) and flow cytometry for apoptosis analysis.
- Manipulation of FUS-CHOP, miR-486, and CDK4 levels using siRNA, inhibitors, and plasmids.
Main Results:
- Myxoid liposarcoma tissues and cells showed decreased miR-486 and increased FUS-CHOP and CDK4.
- FUS-CHOP knockdown suppressed tumor growth, enhanced apoptosis, and increased cleaved Caspase3, effects reversed by miR-486 inhibition.
- miR-486 mimic reduced cell growth and induced apoptosis, effects abolished by CDK4 overexpression.
Conclusions:
- FUS-CHOP promotes myxoid liposarcoma progression by downregulating miR-486, leading to CDK4 upregulation.
- The FUS-CHOP/miR-486/CDK4 axis is a key regulator of proliferation and apoptosis in myxoid liposarcoma.
- FUS-CHOP-siRNA presents a potential therapeutic strategy for myxoid liposarcoma.
