Expression of human kallikrein 1-related peptidase 4 (KLK4) and MET phosphorylation in prostate cancer tissue: immunohistochemical analysis

Abstract

Resistance to or relapse after androgen deprivation therapy (ADT) remains a significant problem in patients with prostate cancer. Several studies have hypothesized that the overexpression of MET and the activating signaling axis in prostate cancer cells are associated with castration-resistant prostate cancer (CRPC). On the other hand, the expression of human kallikrein 1-related peptidase (KLK) 4, which activates plasma HGF activator zymogen, in prostate cancer patients with bone metastasis or advanced stage has also been reported. In this study, we analyzed the expression and phosphorylation of MET along with KLK4 by immunohistochemistry in 62 formalin-fixed paraffin-embedded sections of prostate cancer collected by needle biopsy at our hospital between 2006 and 2011. As a result, the phosphorylation of MET was observed in 56% (35 of 62 cases) and positively correlated with worsening PSA relapse rate in a group of ADT-treated patients (P = 0.0445), suggesting significant correlation with CRPC. Overexpression of KLK4 was observed in patients with high T stage (P = 0.0001) and high Gleason score (P = 0.0146), and the expression was correlated with the phosphorylation of MET (P = 0.0002). Pathologically, strong MET phosphorylation observed in specific architectures in prostate cancer, such as cribriform structures, ill-defined glands or solid patterns, suggested the significance of MET activation in promoting the architectural formation of prostate cancer. In addition, high positivity rate (80%) of phospho-MET staining at high-grade prostatic intraepithelial neoplasia (HGPIN) may indicate the importance of the activating signaling axis in the carcinogenesis of prostate cancer.

Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

“…CCND1 overexpression accounts for cisplatin resistance through cell cycle control and inhibits cellular apoptosis pathway in the most of tumors [30]. Overexpression of KLK4 was observed in patients with high T stage and GS [31] and KLK3 encodes PSA, a widely used biomarker for PCa detection and disease monitoring [32]. KNTC2 encodes the Hec1 protein, which plays an essential role in chromosome segregation by interacting through its coiled-coil domains with several proteins modulating the G 2 /M transition [33].…”

Plasma macrophage-stimulating protein and hepatocyte growth factor levels are associated with prostate cancer progression

“…In addition, compared with control, the environment with low androgen level caused by ADT may lead to elevated HGF concentration in plasma. Several studies report high MET expression in CRPC cells, suggesting the important role of the HGF/MET signaling axis in CRPC [29,30]; however, we were unable to locate studies reporting ADT-induced Fig. 3 Plasma levels (pg/ml) of HGF activator (HGFA) (a) were significantly higher in the CRPC group than in the control group (P \ 0.001).…”

Kallikrein‐related peptidase 4 induces cancer‐associated fibroblast features in prostate‐derived stromal cells

“…Herein, we have confirmed the overexpression of KLK4 in PCa tissues compared to normal prostate as previously demonstrated by several independent studies (Mukai et al ., ; Seiz et al ., ; Veveris‐Lowe et al ., ). In addition, by extending our analysis to nonmalignant prostate lesions, our study is the first to reveal a significant KLK4 overexpression in nonmalignant prostate lesions (BPH, PIN and HGPIN) compared to normal prostate gland.…”

“…KLK4 exerts its biological effects through multiple molecular mechanisms, such as regulation of ECM remodelling (Fuhrman‐Luck et al ., ; Zhu et al ., ), control of activity of growth factor‐ and hormone‐related signalling pathways (Mukai et al ., , ; Sanchez et al ., ), modulation of the proteolytic network (Dong et al ., ; Yoon et al ., ) and cleavage of several membrane‐bound proteins (Lisle et al ., ; Matsumura et al ., ; Ramsay et al ., ,b), notably activation of PARs. Using two different approaches to inhibit PAR1 activation (desensitization and siRNA‐mediated silencing), we identified PAR1 to be predominantly activated by KLK4 in WPMY1 cells.…”

“…KLK4 exerts autocrine effects on cancer cells and paracrine effects on surrounding normal cells, in turn regulating key signalling pathways (Gao et al ., ; Mukai et al ., ; Ramsay et al ., ; Wang et al ., ). Notably, KLK4 activates secreted molecules such as hepatocyte growth factor/scatter factor (HGF‐SF) (Mukai et al ., , ), insulin‐like growth factor (IGF) (Matsumura et al ., ) and TGF‐β (Shahinian et al ., ). KLK4 participates in ECM remodelling (Matsumura et al ., ; Shahinian et al ., ; Zhu et al ., ) and acts directly on target cells through proteolysis of membrane‐tethered proteins, such as the ephrin B4 receptor (Lisle et al ., ) and protease‐activated receptors (PARs) (Gratio et al ., ; Ramsay et al ., ,b; Wang et al ., ).…”