Jiang Bingjie, Zhang Yan, Liu Jian, Tsigkou Anastasia, Rapti Magdalini, Lee Meng Huee
Department of Biological Sciences, Xian Jiaotong Liverpool University, Suzhou 215123, China.
Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, United Kingdom.
Oncotarget. 2017 Apr 4;8(14):22685-22699. doi: 10.18632/oncotarget.15165.
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 T2PEX+TM and T2PEX) are able to interact with MT1-MMP on the cell surface as well as intracellularly. In the case of T2PEX+TM, there is even a clear sign of MT1-MMP:T2PEX+TM aggregation by the side of the nucleus to form aggresomes. In vitro, T2PEX+TM and T2PEX 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 T2PEX 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.
转移性癌细胞表达膜型1-基质金属蛋白酶（MT1-MMP）以降解细胞外基质，从而促进迁移和增殖。金属蛋白酶组织抑制剂（TIMP）-2是MMP的内源性抑制剂。在此，我们描述了一种新型且高效的融合策略，以增强TIMP-2向MT1-MMP的递送。我们发现，与MT1-MMP的血红素结合蛋白+/-跨膜结构域融合的TIMP-2（两种嵌合体分别命名为T2PEX+TM和T2PEX）能够在细胞表面以及细胞内与MT1-MMP相互作用。在T2PEX+TM的情况下，甚至在细胞核旁有MT1-MMP:T2PEX+TM聚集形成聚集体的明显迹象。在体外，T2PEX+TM和T2PEX对子宫颈癌（HeLa）和HT1080纤维肉瘤癌细胞的明胶酶解和侵袭能力的抑制作用明显优于野生型TIMP-2。在小鼠异种移植模型中，我们进一步证明，相对于对照组，T2PEX可使子宫颈癌生长减少85%。总体而言，我们的研究结果表明融合策略作为一种潜在的癌症抑制靶向方法是有效的。
