期刊
ONCOTARGET
卷 8, 期 14, 页码 22685-22699出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.15165
关键词
MT1-MMP; TIMP; cancer; haemopexin; protein engineering
资金
- National Natural Science Foundation of China (NSFC) [31270850]
- Suzhou Industrial Park Supplement Fund
- Research Development Fund, XJTLU
Metastatic cancer cells express Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) to degrade the extracellular matrix in order to facilitate migration and proliferation. Tissue Inhibitor of Metalloproteinase (TIMP)-2 is the endogenous inhibitor of the MMP. Here, we describe a novel and highly effective fusion strategy to enhance the delivery of TIMP-2 to MT1-MMP. We can reveal that TIMP-2 fused to the haemopexin +/- transmembrane domains of MT1-MMP (two chimeras named T2(PEX+TM) and T2(PEX)) are able to interact with MT1-MMP on the cell surface as well as intracellularly. In the case of T2(PEX+TM), there is even a clear sign of MT1-MMP: T2(PEX+TM) aggregation by the side of the nucleus to form aggresomes. In vitro, T2(PEX+TM) and T2(PEX) suppress the gelatinolytic and invasive abilities of cervical carcinoma (HeLa) and HT1080 fibrosarcoma cancer cells significantly better than wild type TIMP-2. In mouse xenograft, we further demonstrate that T2(PEX) diminishes cervical carcinoma growth by 85% relative to the control. Collectively, our findings indicate the effectiveness of the fusion strategy as a potential targeted approach in cancer inhibition.
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