Secretion and Expression of Matrix Metalloproteinase-2 and 9 from Bone Marrow Mononuclear Cells in Myelodysplastic Syndrome and Acute Myeloid Leukemia

Abstract

Background: Matrix metalloproteinase -2 (gelatinase-A, Mr 72,000 type IV collagenase, MMP-2) and -9 (gelatinase-B, Mr 92,000 type IV collagenase, MMP-9) are key molecules that play roles in tumor growth, invasion, tissue remodeling, metastasis and stem-cell regulation by digesting extracellular matrix barriers. MMP-2 and -9 are well known to impact on solid cancer susceptibility, whereas, in hematological malignancies, a paucity of data is available to resolve the function of these regulatory molecules in bone marrow mononuclear cells (BM-MNCs) and stromal cells of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Objectives: The present study aimed to investigate mRNA expression and gelatinase A and B secretion from BM-MNCs in vitro and genotypic associations of MMP-2 (-1306 C/T; rs243865), MMP-9 (-1562 C/T; rs3918242), tissue inhibitor of metalloproteinase -1 (TIMP-1) (372T/C; rs4898, Exon 5) and TIMP-2 (-418G/C; rs8179090) in MDS and AML. Results: The study covered cases of confirmed MDS (n=50), AML (n=32) and healthy controls (n=110). MMP-9 mRNA expression revealed 2 fold increased expression in MDS-RAEB II and 2.5 fold in AML M-4 (60-70% blasts). Secretion of gelatinase-B also revealed the MMP-9 mRNA expression and ELISA data also supported these data. We noted that those patients having more blast crises presented with more secretion of MMP-9 and its mRNA expression. In contrast MMP-9 (-1562 C/T) showed significant polymorphic associations in MDS (p<0.02) and AML (p<0.02). MMP-9 mRNA expression of C/T and T/T genotypes were 1.5 and 2.5 fold increased in MDS and AML respectively. In AML, MMP-2 C/T and T/T genotypes showed 2.0 fold mRNA expression. Only MMP-9 (-1306 C/T) showed significant 4 fold (p<0.001) increased risk with chemical and x-ray exposed MDS, while tobacco and cigarette smokers have 3 fold (p<0.04) risk in AML. Conclusions: In view of our results, MMP-9 revealed synergistic secretion and expression in blast crises of MDS and AML with 'gene' polymorphic effects and is significantly associated with increased risk with tobacco, cigarette and environmental exposure. Release and secretion of these enzymes may influence hematopoietic cell behavior and may be important in the clinical point of view. It may offer valuable tools for diagnosis and prognosis, as well as possible targets for the treatments.

The preterm cervix reveals a transcriptomic signature in the presence of premature prelabor rupture of membranes

“…Consistent with our hypothesis, MMP-2 and MMP-9 increase in response to exogenous BCAAs in the hippocampus of rats 60 and bone Report of the GO terms containing the features PRAM1, FGD3, CEACAM3, and NDRG2 among other genes that mapped to significant features at adjusted value of P < .01 (continued) Original Research OBSTETRICS ajog.org marrowederived cells have been also shown to secrete MMPs. [61][62][63] A similar mechanism for cervical remodeling in TL and PPROM involving bone marrowerecruited cells can be further evidenced by KEGG analysis, in which the osteoclast differentiation pathway is enriched not only in PPROM-PTL comparison (Table 2) but also in TL-PTL (Supplemental Table 3). Osteoclasts are bone marrowederived cells traditionally involved in the degradation of bone matrix 64 and have been described to secrete MMP-2 and MMP-9.…”

Potential for subsets of wt-NPM1 primary AML blasts to respond to retinoic acid treatment

“…Of these c-Cbl [ 24 – 26 ], c-Raf [ 24 , 27 – 29 ], Lyn [ 24 , 28 ], VAV1 [ 26 , 37 , 54 ], and CD38 [ 26 ] have been found partnered in a signalsome that generates a signal that regulates proliferation/differentiation and propels RA-induced differentiation of HL-60 AML cells. Smad2 [ 55 ], MMP9 [ 56 , 57 ] and LCN2 [ 58 ] have been attributed with roles in AML leukemogenesis. HL-60 was included for comparison to the patient samples, and in particular to determine if it shared any signaling signature similarities with AML 94 (Figure 8 ).…”

Curcumin inhibited the growth and invasion of human monocytic leukaemia SHI-1 cellsin vivoby altering MAPK and MMP signalling

“…Over the past decade, it has become evident that, to colonize new tissue, leukaemia cells need to develop a premetastatic niche via extracellular matrix remodelling, which they achieve by releasing MMPs (Shay et al 2015). Studies have confirmed that metalloproteinases, including MMP2 and MMP9, play an important role in the invasion process of various solid tumours by digesting the extracellular matrix barrier (Deryugina and Quigley 2006;Chaudhary et al 2016). Thus in order to minimize treatment-associated mortality, suppression of EMT as well as expression of metalloproteinases may represent a rational alternative strategy for reducing metastatic potential of vimentin.…”