The identification of new predictive biomarkers for human prostate cancer (CaP), especially those that are indicative of invasiveness of the disease will be important for improving clinical management leading to improved survival of patients with CaP. The degradation of extracellular matrix (ECM) and interstitial stroma is a critical event that occurs during the progression and metastasis of CaP. Matriptase, a type II transmembrane serine protease is involved in angiogenesis, degradation of ECM and in progression of some epithelial cancers. Here we establish the clinical significance of matriptase and its inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1) during the progression of human CaP. Expression patterns of matriptase and HAI-1 were determined in primary cultures of normal human prostate epithelial (NHPE) cells, human CaP cells LNCaP, DU-145, CWR22Rν1 and PC-3 and in tissue samples of 92 patients with normal prostate, benign prostate hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and adenocarcinoma of different tumor grades (I-III). The protein and mRNA levels of matriptase were significantly higher in all carcinoma cells as compared with NHPE. Furthermore, highly aggressive PC-3 cells (androgen-independent) exhibited higher levels of mRNA and protein expression of matriptase than all other CaP cells suggesting that matriptase may have a potential role in the aggressiveness and progression of CaP. Conversely, high constitutive mRNA and protein expression of HAI-1 was observed in NHPE, whereas all CaP cells exhibited a reduced expression of HAI-1. Highly aggressive PC-3 cells exhibited lowest expression of HAI-1 mRNA and protein among all CaP cells suggesting a loss of HAI-1 protein in highly advanced and aggressive CaP. On the basis of immunohistochemical staining pattern of CaP specimens, a progressive increase in the protein levels of matriptase was observed with increasing tumor grade in CaP specimens as compared to normal and BPH tissue specimens. The specimens of tumor grade III were found to exhibit the significantly higher expression of matriptase protein than tumor grade I specimens suggesting that matriptase may be involved in the advancement of human CaP. Tissue samples of normal prostate exhibited a high constitutive protein level of HAI-1 compared to BPH and low-grade cancer (grade1) with a progressive loss with increasing tumor grade. Thus, we provide evidence for the first time for over-expression of matriptase with concomitant loss of HAI-1 in human CaP cells and tissue specimens and show that this correlates with the clinical stages of human CaP. We propose a role for matriptase and HAI-1 proteins in CaP development and suggest their potential use as a biomarker for establishing the efficacy of therapeutic and chemopreventive interventions.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]