The essential roles of matrix metalloproteinase-2, membrane type 1 metalloproteinase and tissue inhibitor of metalloproteinase-2 in the invasive capacity of acute monocytic leukemia SHI-1 cells

Leuk Res. 2010 Aug;34(8):1083-90. doi: 10.1016/j.leukres.2010.01.016. Epub 2010 Feb 6.

Abstract

The frequency of extramedullary infiltration (EMI) in acute myeloblastic leukemia (AML) is reported up to 40% and most prevalent in myelo-monoblastic and monoblastic subtypes of AML (M4 and M5 according to FAB classification). The majority of patients with EMI suffered poor prognosis. To explore mechanism underlying EMI, we analyzed SHI-1 cells, a highly invasive human acute monocytic leukemia cell line, and found their strong expression of matrix metalloproteinase 2 (MMP-2), membrane type 1 MMP (MT1-MMP) and tissue inhibitor of metalloproteinase 2 (TIMP-2). SHI-1 cells showed higher invasive ability to traverse reconstituted basement membranes (Matrigel) and stronger activation of proMMP-2 than other leukemia cell line such as NB4, K562, U937 and THP-1 cells. When co-cultured with bone marrow stromal cells (BMSCs), the invasive capacity and proMMP-2 activation of SHI-1 cells enhanced remarkably. Furthermore, the inhibition of MMP-2, MT1-MMP, or TIMP-2 by small interfering RNA (siRNA) substantially impaired SHI-1 cells invasion and decreased proMMP-2 activation. In the contrast, up-regulated expression of TIMP-2 for 2-3 folds level increased cell invasion and proMMP-2 activation. These results demonstrated that constitutively high expression of MMP-2, MT1-MMP and TIMP-2 in SHI-1 cells facilitated cell invasion by promoting proMMP-2 activation. Moreover, up-regulation of TIMP-2 exhibited not a repressive but an activating effect on SHI-1 cells invasion. Our study indicated that increasing TIMP-2 in AML patients with EMI may potentially cause adverse effects, particularly in patients containing high levels of MMP-2 and MT1-MMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Collagen / metabolism
  • Drug Combinations
  • Humans
  • Immunoblotting
  • Laminin / metabolism
  • Leukemia, Monocytic, Acute / genetics
  • Leukemia, Monocytic, Acute / metabolism*
  • Leukemia, Monocytic, Acute / pathology*
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism*
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase Inhibitors
  • Neoplasm Invasiveness
  • Proteoglycans / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Tissue Inhibitor of Metalloproteinase-2 / antagonists & inhibitors
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism*
  • Tumor Cells, Cultured

Substances

  • Drug Combinations
  • Laminin
  • Matrix Metalloproteinase Inhibitors
  • Proteoglycans
  • RNA, Messenger
  • RNA, Small Interfering
  • matrigel
  • Tissue Inhibitor of Metalloproteinase-2
  • Collagen
  • Matrix Metalloproteinase 2
  • MMP14 protein, human
  • Matrix Metalloproteinase 14