Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α

Leah A Marquez-Curtis,Neeta Shirvaikar,Anna Janowska-Wieczorek,Loree M Larratt,A Robert Turner,Imran Mirza,Amir Surmawala

doi:10.3390/cancers4030743

Leah A Marquez-Curtis, Neeta Shirvaikar + Show 5 more

Open Access

https://doi.org/10.3390/cancers4030743

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Journal: Cancers	Publication Date: Jul 25, 2012
Citations: 49	License type: CC BY 4.0

Affiliation: Canadian Blood Services, University of Alberta

Abstract

Membrane type-1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion, as well as trafficking of normal hematopoietic cells, and acts as a physiologic activator of proMMP-2. In this study we examined MT1-MMP expression in primary acute myeloid leukemia (AML) cells. Because tumor necrosis factor (TNF)-α is known to be elevated in AML, we also investigated the effect of TNF-α on MT1-MMP expression. We found (i) MT1-MMP mRNA expression in 41 out of 43 primary AML samples tested; (ii) activation of proMMP-2 in co-cultures of AML cells with normal bone marrow stromal cells; and (iii) inhibition of proMMP-2 activation and trans-Matrigel migration of AML cells by gene silencing using MT1-MMP siRNA. Moreover, recombinant human TNF-α upregulated MT1-MMP expression in AML cells resulting in enhanced proMMP-2 activation and trans-Matrigel migration. Thus, AML cells express MT1-MMP and TNF-α enhances it leading to increased MMP-2 activation and most likely contributing to the invasive phenotype. We suggest that MT1-MMP, together with TNF-α, should be investigated as potential therapeutic targets in AML.

Highlights

Matrix metalloproteinases (MMPs) comprise a family of Zn2+-binding, Ca2+-dependent endopeptidases whose expression and activity are upregulated in most cancers [1,2,3,4,5]
We showed that tumor necrosis factor (TNF)-α a naturally occurring cytokine involved in normal inflammatory and immune responses, had the most pronounced stimulatory effect on the secretion of MMP-2 by normal hematopoietic stem/progenitor cells (HSPC) [9]
We found, using quantitative RT-PCR analysis, that both steady-state and mobilized MNC and mobilized CD34+ cells from normal peripheral blood (PB) have significantly lower Membrane type-1 matrix metalloproteinase (MT1-MMP) mRNA expression compared to MNC from acute myeloid leukemia (AML) PB (Figure 1C)

Summary

Introduction

Matrix metalloproteinases (MMPs) comprise a family of Zn2+-binding, Ca2+-dependent endopeptidases whose expression and activity are upregulated in most cancers [1,2,3,4,5]. They have the capacity to degrade virtually every component of the extracellular matrix (ECM) [6,7]. We showed that tumor necrosis factor (TNF)-α a naturally occurring cytokine involved in normal inflammatory and immune responses, had the most pronounced stimulatory effect on the secretion of MMP-2 by normal hematopoietic stem/progenitor cells (HSPC) [9]. Activation of proMMP-2 involves binding of MT1-MMP to tissue inhibitor of metalloproteinases (TIMP)-2, and the resulting binary complex acts as a receptor for proMMP-2, which is cleaved by a second MT1-MMP molecule generating a fully active

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