Matrix metalloproteinase-9 is differentially expressed in nonfunctioning invasive and noninvasive pituitary adenomas and increases invasion in human pituitary adenoma cell line.
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-alpha, and PKC-delta small interfering (si)RNAs but not by hispidin (PKC-beta 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-alpha siRNA, or PKC-delta siRNA. These results demonstrate that MMP-9 and PKC-alpha or PKC-delta may provide putative therapeutic targets for the control of PA dural invasion.
Hussaini
Isa M
IM
Department of Pathology, 415 Lane Rd., Box 800904, University of Virginia, Charlottesville, VA 22908, USA. imh5c@virignia.edu
Trotter
Christy
C
Zhao
Yunge
Y
Abdel-Fattah
Rana
R
Amos
Samson
S
Xiao
Aizhen
A
Agi
Crystal U
CU
Redpath
Gerard T
GT
Fang
Zixing
Z
Leung
Gilberto K K
GK
Lopes
Maria Beatriz S
MB
Laws
Edward R
ER
D000236:Adenoma / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000201:enzymology / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011753:Pyrones / Q000494:pharmacology; D034741:RNA, Small Interfering; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011753:Pyrones; D034741:RNA, Small Interfering; C016658:phorbolol myristate acetate; D011493:Protein Kinase C; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate; C007946:hispidin