Riddick A C P, Shukla C J, Pennington C J, Bass R, Nuttall R K, Hogan A, Sethia K K, Ellis V, Collins A T, Maitland N J, Ball R Y, Edwards D R
Norfolk and Norwich University Hospital NHS Trust, Norwich NR4 7UY, UK.
Br J Cancer. 2005 Jun 20;92(12):2171-80. doi: 10.1038/sj.bjc.6602630.
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.
基质金属蛋白酶（MMP）和丝氨酸蛋白酶家族的细胞外蛋白酶参与肿瘤生长和转移的多个方面。我们运用定量实时逆转录聚合酶链反应（RT-PCR）分析方法，对44例人类前列腺癌和23例良性前列腺标本中这些酶及其天然抑制剂的表达进行了全面研究。我们发现，与良性前列腺组织相比，恶性组织中MMP10、15、24、25和26、尿激酶型纤溶酶原激活物受体（uPAR）和纤溶酶原激活物抑制剂-1（PAI1），以及新鉴定的丝氨酸蛋白酶组织蛋白酶H和matriptase-1（MTSP1）的表达增加。相反，癌标本中MMP2和MMP23、maspin以及蛋白酶抑制剂金属蛋白酶组织抑制剂3（TIMP3）、TIMP4和RECK（富含Kazal基序的逆转诱导富含半胱氨酸蛋白）的表达显著降低。MMP15和MMP26的表达与Gleason评分呈正相关，而TIMP3、TIMP4和RECK的表达与Gleason评分呈负相关。利用前列腺癌根治术标本来源的原发性恶性上皮和基质细胞培养物，评估了失调基因表达的细胞定位。MMP10和25、组织蛋白酶H、MTSP1和maspin主要在上皮细胞中表达，而TIMP 3和4、RECK、MMP2和23、uPAR和PAI1主要由基质细胞产生。这些数据首次对人类前列腺癌中MMP及其抑制剂的表达和定位进行了全面定量分析，从而确定了几个参与蛋白水解的基因作为潜在的预后指标，特别是组织蛋白酶H、MTSP1、MMP26、PAI1、uPAR、MMP15、TIMP3、TIMP4、maspin和RECK。
