Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells
S. Philip et al., Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells, J BIOL CHEM, 276(48), 2001, pp. 44926-44935
Matrix metalloproteinases (MMPs) degrade the extracellular matrix (ECM) and
play critical roles in tissue repair, tumor invasion, and metastasis. MMPs
are regulated by different cytokines, ECM proteins, and other factors. How
ever, the molecular mechanisms by which osteopontin (OPN), an ECM protein,
regulates ECM invasion and tumor growth and modulates MMP activation in B16
F10 cells are not well defined. We have purified OPN from human milk and sh
own that OPN induces pro-MMP-2 production and activation in these cells. Mo
reover, our data revealed that OPN-induced membrane type 1 (MT1) MMP expres
sion correlates with translocation of p65 (nuclear factor-kappaB (NF-kappaB
)) into the nucleus. However, when the super-repressor form of I kappaB alp
ha (inhibitor of NF-kappaB) was transfected into cells followed by treatmen
t with OPN, no induction of MT1-MMP expression was observed, indicating tha
t OPN activates pro-MMP-2 via an NF-kappaB-mediated pathway. OPN also enhan
ced cell migration and ECM invasion by interacting with alpha (v)beta (3) i
ntegrin, but these effects were reduced drastically when the MMP-2-specific
antisense S-oligonucleotide was used to suppress MMP-2 expression. Interes
tingly, when the OPN-treated cells were injected into nude mice, the mice d
eveloped larger tumors, and the MMP-2 levels in the tumors were significant
ly higher than in controls. The proliferation data indicate that OPN increa
ses the growth rate in these cells. Both tumor size and MMP-2 expression we
re reduced dramatically when anti-MMP-2 antibody or antisense S-oligonucleo
tide-transfected cells were injected into the nude mice. To our knowledge,
this is the first report that MMP-2 plays a direct role in OPN-induced cell
migration, invasion, and tumor growth and that demonstrates that OPN-stimu
lated MMP-2 activation occurs through NF-kappaB-mediated induction of MT1-M
MP.