Oncotarget

Research Papers:

Ensnaring membrane type 1-matrix metalloproteinase (MT1-MMP) with tissue inhibitor of metalloproteinase (TIMP)-2 using the haemopexin domain of the protease as a carrier: a targeted approach in cancer inhibition

Bingjie Jiang, Yan Zhang, Jian Liu, Anastasia Tsigkou, Magdalini Rapti and Meng Huee Lee _

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Oncotarget. 2017; 8:22685-22699. https://doi.org/10.18632/oncotarget.15165

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Abstract

Bingjie Jiang1, Yan Zhang1, Jian Liu1, Anastasia Tsigkou1, Magdalini Rapti2, Meng Huee Lee1

1Department of Biological Sciences, Xian Jiaotong Liverpool University, Suzhou 215123, China

2Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, United Kingdom

Correspondence to:

Meng Huee Lee, email: Meng.lee@xjtlu.edu.cn

Keywords: MT1-MMP, TIMP, cancer, haemopexin, protein engineering

Received: November 16, 2016     Accepted: January 24, 2017     Published: February 07, 2017

ABSTRACT

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.


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