MMPs are enzymes produced by stromal or tumor cells and are involved in tumor progression. TIMPs are induced in stromal cells to regulate the proteinase reactions. They are closely related to a series of pathological processes. The imbalance between MMP and TIMP plays a critical role in cancer invasion and metastasis (20
The role of MMPs and TIMPS in RCC growth, metastasis and angiogenesis has been the focus of intense investigation for a number of years. Awakura et al
demonstrated by univariate analysis that TIMP-2 is a significant prognostic factor (1
). Kawata et al
identified that the expression of TIMP-2 has an essential correlation with the expression of MMP-2, which may have a correlation with the prognosis of CCRCC. Moreover, the authors indicated that nuclear grade and TIMP-2 are significant prognostic factors of CCRCC and that patients with tumors with a high pathological grade and strongly expressed MMP-9 and TIMP-2 have a poor outcome (23
). Miyata et al
reviewed tissue samples of 156 RCC patients and demonstrated that MMP-7 affects tumor progression by regulating invasion and angiogenesis and is a predictor of poor prognosis by multivariate analysis (25
). However, another study reported that MMP-7 expression is not associated with clinicopathological features, including grade, invasion and metastasis in a number of cancers (26
). Thus, there is a difference of opinion regarding the clinical significance of MMP-7 in cancers.
In the current study, we focused on the roles of MMP-7 and TIMP-2 in the tissue of 98 CCRCC patients in relation to the clinicopathological characteristics of tumors, including pathological grade and clinical stage, and the survival rate of the patients, using tissue microarray, immunohistochemistry and RT-PCR. The results of immunohistochemical analysis demonstrated that the expression level of MMP-7 in CCRCC was significantly higher than in the CG. Moreover, high MMP-7 expression was correlated with the degree of malignancy, including high grade and high stage. In addition, univariate survival rate analysis demonstrated that patients with an elevated expression of MMP-7 in the CCRCC tissue were predicted to have a poor prognosis. TIMP-2 expression level in CCRCC was clearly lower than in the CG and the high expression correlated with low grade and low stage. Univariate survival rate analysis demonstrated that, contrary to MMP-7 expression, patients with an elevated expression of TIMP-2 had a good survival rate. Correlation analysis revealed negative correlations between MMP-7 and TIMP-2 expression levels. Cox multivariate survival rate analysis demonstrated positive correlations between MMP-7 expression level and a high potential for tumor invasion and metastasis, and a poor prognosis. Through RT-PCR analysis, we also confirmed the high expression of MMP-7 and low expression of TIMP-2 in cases with high pathological grade and clinical stage.
These findings revealed that the expression levels of MMP-7 and TIMP-2 in CCRCC tissues are related to malignant progression in RCC and also to survival rate following tumor removal. Therefore, expression of these proteins may be considered indicators of progression in CCRCC tumors and prognostic predictors in CCRCC patients. These findings also indicate that MMP-7 is an independent prognostic factor but TIMP-2 is not, which differs from the conclusions of other studies (23
). Thus, MMP-7 and TIMP-2 may be useful molecular markers for evaluating prognosis in CCRCC patients.
In conclusion, we demonstrated for the first time that MMP-7 is associated with TIMP-2 expression in CCRCC. The concentrations of MMP-7 and TIMP-2 in the tissue of 98 CCRCC patients were assessed in relation to pathological grade, clinical stage and survival rate. Upregulated expression of MMP-7 and downregulated expression of TIMP-2 in CCRCC have significant clinicopathological associations with the aggressiveness observed for this tumor. In addition, we identified that elevated levels of MMP-7 in cancer tissues are a strong and independent predictor of poor prognosis.
Therefore, MMP-7 and TIMP-2 may be useful molecular markers for evaluating prognosis in CCRCC patients and MMP-7 may be a new target for the prevention of tumor development and improvement of survival rate.