Clinical evidence for a protective role of lipocalin-2 against MMP-9 autodegradation and the impact for gastric cancer.
Recently, complexes of matrix metalloproteinase matrix metalloproteinase-9 (MMP-9) with lipocalin-2 (neutrophil gelatinase-associated lipocalin) were found in the urine obtained from breast cancer patients, while these were completely absent in that obtained from healthy controls. In vitro data suggested a possible role for lipocalin-2 in the protection of MMP-9 against autolysis. To establish this effect in vivo, we determined the presence of MMP-9, lipocalin-2 and their complex in tumour tissue from 81 gastric cancer patients. The effect of the presence of the individual parameters, the complexes, and the inhibitors TIMP-1 and TIMP-2 on MMP-9 activity was evaluated with a bioactivity assay. Immuno-histochemical (double) staining identified epithelial cells as the most likely cellular source. Finally, evaluation of all these parameters with clinico-pathological scores revealed that tumour MMP-9/lipocalin-2 complexes were significantly related with the classifications of Laurén and WHO, and highly associated with worse survival in Cox's univariate (HR 2.087, P=0.006) and multivariate analyses (HR 2.095, P=0.025).
Kubben
Frank J G M
FJ
Department of Gastroenterology - Hepatology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
Sier
Cornelis F M
CF
Hawinkels
Lukas J A C
LJ
Tschesche
Harald
H
van Duijn
Wim
W
Zuidwijk
Kim
K
van der Reijden
Johan J
JJ
Hanemaaijer
Roeland
R
Griffioen
Gerrit
G
Lamers
Cornelis B H W
CB
Verspaget
Hein W
HW
D000209:Acute-Phase Proteins / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000071068:Lipocalin-2; D054834:Lipocalins / Q000378:metabolism / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality
D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D020780:Matrix Metalloproteinase 9