Pharmaceutical Sciences Faculty Publications

Title

Matrix Metalloproteinase-9 Is Differentially Expressed in Nonfunctioning Invasive and Noninvasive Pituitary Adenomas and Increases Invasion in Human Pituitary Adenoma Cell Line

Document Type

Article

Publication Date

1-2007

Journal Title

The American Journal of Pathology

ISSN

0002-9440

Volume

170

Issue

1

First Page

356

Last Page

365

DOI

http://dx.doi.org/10.2353/ajpath.2007.060736

PubMed ID

17200207

PubMed Central® ID

PMC1762693

Abstract

The complete resection of pituitary adenomas (PAs) is unlikely when there is an extensive local dural invasion and given that the molecular mechanisms remain primarily unknown. DNA microarray analysis was performed to identify differentially expressed genes between nonfunctioning invasive and noninvasive PAs. Gene clustering revealed a robust eightfold increase in matrix metalloproteinase (MMP)-9 expression in surgically resected human invasive PAs and in the (nonfunctioning) HP75 human pituitary tumor-derived cell line treated with phorbol-12-myristate-13-acetate; these results were confirmed by real-time polymerase chain reaction, gelatin zymography, reverse transcriptase-polymerase chain reaction, Western blot, immunohistochemistry, and Northern blot analyses. The activation of protein kinase C (PKC) increased both MMP-9 activity and expression, which were blocked by some PKC inhibitors (Gö6976, bisindolylmaleimide, and Rottlerin), PKC-α, and PKC-δ small interfering (si)RNAs but not by hispidin (PKC-β inhibitor). In a transmembrane invasion assay, phorbol-12-myristate-13-acetate (100 nmol/L) increased the number of invaded HP75 cells, a process that was attenuated by PKC inhibitors, MMP-9 antibody, PKC-α siRNA, or PKC-δ siRNA. These results demonstrate that MMP-9 and PKC-α or PKC-δ may provide putative therapeutic targets for the control of PA dural invasion.

Keywords

pituitary adenomoas, MMP-9, protein kinase, RNA, DNA, enzymes