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.
Keywords: acute myeloid leukemia; membrane type 1-matrix metalloproteinase; matrix metalloproteinase-2; tumor necrosis factor-α
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Marquez-Curtis, L.A.; Shirvaikar, N.; Turner, A.R.; Mirza, I.; Surmawala, A.; Larratt, L.M.; Janowska-Wieczorek, A. Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α. Cancers 2012, 4, 743-762.
Marquez-Curtis LA, Shirvaikar N, Turner AR, Mirza I, Surmawala A, Larratt LM, Janowska-Wieczorek A. Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α. Cancers. 2012; 4(3):743-762.
Marquez-Curtis, Leah A.; Shirvaikar, Neeta; Turner, A. Robert; Mirza, Imran; Surmawala, Amir; Larratt, Loree M.; Janowska-Wieczorek, Anna. 2012. "Membrane Type-1 Matrix Metalloproteinase Expression in Acute Myeloid Leukemia and Its Upregulation by Tumor Necrosis Factor-α." Cancers 4, no. 3: 743-762.