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Surgery. 2003 Aug;134(2):293-9.

Glial cell-derived neurotrophic factor upregulates the expression and activation of matrix metalloproteinase-9 in human pancreatic cancer.

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  • 1Section of Gastrointestinal Surgery, the David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.

Abstract

BACKGROUND:

We have previously reported that the glial cell-derived neurotrophic factor (GDNF) promotes pancreatic cancer cell invasion in vitro. The purpose of this study was to determine whether GDNF regulates the expression and activation of matrix metalloproteinase-9 (MMP-9) in human pancreatic cancer cells.

METHODS:

We used human pancreatic cancer cell line MIA PaCa-2. The effect of GDNF on mRNA and protein expression was measured by Northern blot, Western blot and enzyme-linked immunosorbent assay. MMP proteolytic activity was detected by gelatin zymography. To determine which intracellular pathways were involved, we used the following inhibitors: tyrosine kinase inhibitor Genistein, MEK-1 inhibitor PD98059 and PI3-K inhibitor Wortmannin.

RESULTS:

GDNF increased MMP-9 mRNA and protein expression in MIA PaCa-2 cells in a dose-dependent manner. Treatment with GDNF enhanced gelatinolytic activity of the pro and active form of MMP-9. Inhibitor experiments showed that the expression and activity of pro MMP-9 was totally inhibited by Genistein and partially by Wortmannin, whereas PD98059 had no effect. All three compounds inhibited the activity of the active form of MMP-9.

CONCLUSIONS:

GDNF upregulates the expression and enzymatic activity of MMP-9 through different signaling pathways in MIA PaCa-2. These findings suggest that GDNF modulates MMP-9 expression and activation, and this may promote pancreatic cancer invasion.

PMID:
12947332
DOI:
10.1067/msy.2003.239
[PubMed - indexed for MEDLINE]
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