Increased expression of matrix metalloproteinase 9 correlates with poor prognostic variables in renal cell carcinoma.
BACKGROUND
MMP2 and MMP9 are two gelatinolytic enzymes, which are key regulators of tumor invasion and metastasis. This study aimed to clarify the prognostic significance of MMP2 and MMP9 with particular regard to their transcript levels, enzymatic activities in renal cell carcinomas (RCCs).


METHODS
Through cDNA array, the differential expression of the MMP superfamily was evaluated in RCC. Various properties of MMP2 and MMP9 were quantified, in 178 patients with RCC, based on the Heidelberg classification. Of these, 145 cases including 16 fresh-frozen cases were available for MMP2 and MMP9 transcript level evaluation. In addition, gelatinolytic activity was assessed by zymography in 16 other fresh-frozen samples from new RCC cases.


RESULTS
MMP2, 9, 11, 14, and 16 were upregulated in the conventional RCC in comparison with the chromophobe RCC, whereas MMP1, 11 and 16 were pronounced in papillary RCC. MMP9 transcript levels were strongly associated with the MMP9 enzymatic activity (p=0.001), and therefore, with disease-free survival (p=0.001) and metastasis (p=0.011). Gelatinolytic activity of MMP9 by zymography was strongly associated with MMP9 mRNA expression, which was more intense in 'conventional' RCC than in 'chromophobe' RCC (p=0.001), irrespective of tumor grade or stage. MMP9 was proven to be a significant prognostic predictor by multi-variate survival analysis (p=0.0054). MMP2 enzymatic activity disappeared in spite of its constant transcript expression in RCC.


CONCLUSIONS
MMP9 appears to be regulated at the transcript level, whereas MMP2 is regulated at the posttranscriptional level. Poor survival with a high frequency of metastases in 'conventional' RCC is associated with MMP9, which exhibits a high transcriptional level, and a high gelatinolytic activity. As a result, MMP9 may be a candidate of predictors of disease-free survival in RCC.
Cho
Nam Hoon
NH
Yonsei University College of Medicine, Department of Pathology, Seadaemoon-ku, Shinchon-dong 134, 120-752 Seoul, Republic of Korea. cho1988@yumc.yonsei.ac.kr
Shim
Hyo Sub
HS
Rha
Sun Young
SY
Kang
Suki Hee
SH
Hong
Sung Hui
SH
Choi
Young Deuk
YD
Hong
Sung Jun
SJ
Cho
Sang Ho
SH
D002292:Carcinoma, Renal Cell / Q000201:enzymology*; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D015854:Up-Regulation
D020782:Matrix Metalloproteinases; D020780:Matrix Metalloproteinase 9