Identification of degradome components associated with prostate cancer progression by expression analysis of human prostatic tissues

Abstract

Extracellular proteases of the matrix metalloproteinase (MMP) and serine protease families participate in many aspects of tumour growth and metastasis. Using quantitative real-time RT -PCR analysis, we have undertaken a comprehensive survey of the expression of these enzymes and of their natural inhibitors in 44 cases of human prostate cancer and 23 benign prostate specimens. We found increased expression of MMP10, 15, 24, 25 and 26, urokinase plasminogen activator-receptor (uPAR) and plasminogen activator inhibitor-1 (PAI1), and the newly characterised serine proteases hepsin and matriptase-1 (MTSP1) in malignant tissue compared to benign prostate tissue. In contrast, there was significantly decreased expression of MMP2 and MMP23, maspin, and the protease inhibitors tissue inhibitor of metalloproteinase 3 (TIMP3), TIMP4 and RECK (reversion-inducing cysteine-rich protein with Kazal motifs) in the cancer specimens. The expression of MMP15 and MMP26 correlated positively with Gleason score, whereas TIMP3, TIMP4 and RECK expression correlated negatively with Gleason score. The cellular localisation of the expression of the deregulated genes was evaluated using primary malignant epithelial and stromal cell cultures derived from radical prostatectomy specimens. MMP10 and 25, hepsin, MTSP1 and maspin showed predominantly epithelial expression, whereas TIMP 3 and 4, RECK, MMP2 and 23, uPAR and PAI1 were produced primarily by stromal cells. These data provide the first comprehensive and quantitative analysis of the expression and localisation of MMPs and their inhibitors in human prostate cancer, leading to the identification of several genes involved in proteolysis as potential prognostic indicators, in particular hepsin, MTSP1, MMP26, PAI1, uPAR, MMP15, TIMP3, TIMP4, maspin and RECK.

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

“…While no true functional conclusions can be drawn as to the roles of the MMPs TIMPs, growth factors or receptors profiled, the upregulation of such a broad spectrum of the MMP family suggests they are an integral part of the complex pathways involved in bladder tumour progression. Studies have demonstrated upregulation of multiple members of the MMP family in other tumour types including prostate and glioblastoma, but the expression patterns vary significantly between tissue types (Nuttall et al, 2003;Riddick et al, 2005). In a recent study by Martinez et al (2005), a wide spectrum of MMPs were found to be upregulated in early murine colonic adenomas; those MMPs located on chromosome 9 showed significantly greater upregulation that those expressed on other chromosomes, suggesting a shared regulatory mechanism resulting in coordinated deregulation of expression in tumour tissue.…”

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

“…Members of the TTSP family, such as hepsin and MT-SP1, are highly expressed in many cancers, including those of the prostate, breast, colon, and ovary (1)(2)(3)(4)(5)(6)(7)(8)(9). Both overexpression and inhibition studies have supported the role of MT-SP1 in tumorigenesis and tumor growth.…”

TMEFF2 shedding is regulated by oxidative stress and mediated by ADAMs and transmembrane serine proteases implicated in prostate cancer

“…Prominent TTSPs involved in PCa progression include matriptase‐1, matriptase‐2 and hepsin. Matriptase‐1 overexpression correlates with Gleason score (Riddick et al, 2005) promoting cell invasion, metastasis and prostate tumour growth (Sanders et al, 2006; Ko et al, 2015) by regulating MET signalling in PCa. Interestingly, matriptase‐1 interacts with a close relative of TMEFF2, TMEFF1, where the EGF‐like domain of TMEFF1 binds to the matriptase‐1 CUB domain (Ge et al, 2006).…”