Determination of imbalance between MMP-2 and TIMP-2 in human neuroblastoma by reverse-transcription polymerase chain reaction and its correlation with tumor progression.
OBJECTIVE
The matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) have been implicated in tumor invasion and metastasis. Net matrix degradation and proteolysis depend on the critical local balance between MMPs/TIMP-2. We attempted to determine their expression balance and to evaluate its importance with tumor progression.


METHODS
Expressions of MMP-2, MMP-9, and TIM P-2 mRNAs was quantified by reverse-transcription polymerase chain reaction (RT-PCR) in tumor tissues from 25 neuroblastoma patients.


RESULTS
MMP-2, MMP-9, and TIMP-2 expression was observed in all the samples but with different trends. Increased expressions of MMP-2 mRNA was evident in advanced stages (Evans' stage III and IV; P = .02; unpaired ttest), and in patients who died of progressive disease (P = .0001). Whereas, the expressions of MMP-9 and TIMP-2 had no such significant association with clinical stages and prognosis. The ratio of MMP-2/TIMP-2 mRNAs was significantly higher in the advanced stages versus early stages (mean +/- SD = 1.66+/-0.65 and 1.11+/-0.34, respectively; P = .02) and in patients who died of progressive disease versus alive patients (mean = 2.13+/-0.78 and 1.21+/-0.36, respectively; P = .0006).


CONCLUSIONS
Coexpression of MMPs and TIMP-2 in neuroblastoma indicates the need to evaluate their expression balance. Significantly higher expression of MMP-2 mRNA and increased ratio of MMP-2 and TIMP-2 mRNAs in advanced stages or patients who have died of progressive disease suggests an association between elevated MMP-2 expression and poor prognosis. To establish the role of enzyme to inhibitor mRNA ratio as a reliable predictor, cohort studies with significant number of cases may be carried out.
Ara
T
T
Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Suita City, Japan.
Kusafuka
T
T
Inoue
M
M
Kuroda
S
S
Fukuzawa
M
M
Okada
A
A
D001483:Base Sequence; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009841:Oligonucleotides / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
D009841:Oligonucleotides; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9