Underexpression of MMP-2 and its regulators, TIMP2, MT1-MMP and IL-8, is associated with prostate cancer

Abstract

Prostate cancer (PCa) is a common disease with a multifactorial and complex etiology. It is the most common malignancy in the male and the second leading cause of death in many countries, including Brazil. Estimates for 2011 indicate that 903,500 new cases and 258,400 deaths relatVol. 38 (2): 167-174; March -April, 2012 Objective: Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their regulators. The purpose of this study was to investigate whether MMP-2 and its specifi c regulators, TIMP-2, MT1-MMP and IL-8, are expressed in a reproducible, specifi c pattern and if the profi les are related to prognosis and clinical outcome of prostate cancer (PCa). Materials and Methods: MMP-2, TIMP-2, MT1-MMP and IL-8 expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in freshly frozen malignant and benign tissue specimens collected from 79 patients with clinically localized PCa who underwent radical prostatectomies. The control group consisted of 11 patients with benign prostate hyperplasia (BPH). The expression profi le of the MMP-2 and its regulators were compared using Gleason scores, pathological stage, pre-operative PSA levels and the fi nal outcome of the PCa. Results: The analysis of 79 specimens of PCa revealed that MMP-2, TIMP-2, MT1-MMP and IL-8 were underexpressed at 60.0%, 72.2%, 62.0% and 65.8%, respectively, in malignant prostatic tissue in relation to BPH samples. Considering the prognostic parameters, we demonstrated that high Gleason score tumors (≥ 7) overexpressed MMP-2 (p = 0.048) and TIMP-2 (p = 0.021), compared to low Gleason score tumors (< 7). Conclusion: We have demonstrated that MMP-2 and its regulators are underexpressed in PCa. Alternatively, overexpression of MMP-2 and TIMP-2 was related to higher Gleason score tumors. We postulate that alterations in metalloproteinase expression may be important in the control of tissue homeostasis related to prostate carcinogenesis and tumor behavior. Underexpression of MMP-2 and its

Membrane-type matrix metalloproteinases: expression, roles in metastatic prostate cancer progression and opportunities for drug targeting

“…Once again, a positive correlation with Gleason score was observed [21] . This reinforced an earlier study by the same group (79 prostate cancer patients), which indicated that MT1-MMP expression was higher in patient samples with Gleason scores ≥ 7, though that dataset only exhibited marginal statistical significance [23] .…”

Loss of TIMP-1 immune expression and tumor recurrence in localized prostate cancer

“…In our cases, MMP-2 and MMP-14 were immune-expressed by the majority of PC cases (77.7%); on the contrary, the MMP-2 and MMP 14 genes were found to be under-expressed in most cases of the PC cases ( 5 ). Our results are similar to those published by Lichtinghagen et al (2002) ( 17 ), who showed MMP-2 under-expression in prostate cancer tissue using RT-PCR.…”

“…Moreover, the levels of MMP-9 were higher in patients with preoperative PSA>10ng/mL, and most importantly in those who have presented biochemical recurrence ( 8 ). We also noted that TIMP-2, MT1-MMP and IL8 were overexpressed and would be possibly responsible for the decrease in MMP-2 expression in PC tissue ( 5 ).…”

“…Within the MMP family, Matrix Metallproteinase 2 (MMP-2) (gelatinase A, 72 kDa) and Matrix Metalloproteinase 9 (MMP-9) (gelatinase B, 92 kDa) cleave type IV collagen and gelatin, which are the main structural components of the basal membrane ( 1 ). MMP-9 and MMP-2 expression has been implicated in the development and progression of many tumors, such as bladder ( 2 ), colorectal ( 3 ), lung cancer ( 4 ) and prostate cancer ( 5 ).…”

Polymorphisms in MMP-2 and TIMP-2 in Turkish patients with prostate cancer

“…The central role of MT1-MMP in inducing oxidative stress in prostate cancer was proven by Nguyen et al (18). Reis et al investigated the expression levels of MMPs and TIMPs in 2 independent studies (19,20). They examined the expression levels of MMP-2 and its regulators (TIMP-2, MT1-MMP, IL-8, and MMP-9) and its inhibitor, TIMP-1, in prostate cancer.…”