Affiliation:
1. Department of Pathology University of Helsinki and Helsinki University Hospital Helsinki Finland
2. Department of Urology University of Helsinki and Helsinki University Hospital Helsinki Finland
3. Research Program in Systems Oncology University of Helsinki Helsinki Finland
4. Department of Clinical Chemistry and Haematology University of Helsinki and Helsinki University Hospital Helsinki Finland
5. iCAN‐Digital Precision Cancer Medicine Flagship Helsinki Finland
6. Laboratory of Molecular Oncology, Department of Oncology University of Helsinki Helsinki Finland
7. Department of Pathology and Laboratory Medicine Mount Sinai Hospital Toronto Ontario Canada
8. Department of Laboratory Medicine and Pathobiology University of Toronto Toronto Ontario Canada
9. Department of Biomedical Engineering, School of Medicine Emory University Atlanta Georgia USA
Abstract
AbstractWe aimed to study mRNA levels and prognostic impact of all 15 human kallikrein‐related peptidases (KLKs) and their targets, proteinase‐activated receptors (PARs), in surgically treated prostate cancer (PCa). Seventy‐nine patients with localized grade group 2‐4 PCas represented aggressive cases, based on metastatic progression during median follow‐up of 11 years. Eighty‐six patients with similar baseline characteristics, but no metastasis during follow‐up, were assigned as controls. Transcript counts were detected with nCounter technology. KLK12 protein expression was investigated with immunohistochemistry. The effects of KLK12 and KLK15 were studied in LNCaP cells using RNA interference. KLK3, ‐2, ‐4, ‐11, ‐15, ‐10 and ‐12 mRNA, in decreasing order, were expressed over limit of detection (LOD). The expression of KLK2, ‐3, ‐4 and ‐15 was decreased and KLK12 increased in aggressive cancers, compared to controls (P < .05). Low KLK2, ‐3 and ‐15 expression was associated with short metastasis‐free survival (P < .05) in Kaplan‐Meier analysis. PAR1 and ‐2 were expressed over LOD, and PAR1 expression was higher, and PAR2 lower, in aggressive cases than controls. Together, KLKs and PARs improved classification of metastatic and lethal disease over grade, pathological stage and prostate‐specific antigen combined, in random forest analyses. Strong KLK12 immunohistochemical staining was associated with short metastasis‐free and PCa‐specific survival in Kaplan‐Meier analysis (P < .05). Knock‐down of KLK15 reduced colony formation of LNCaP cells grown on Matrigel basement membrane preparation. These results support the involvement of several KLKs in PCa progression, highlighting, that they may serve as prognostic PCa biomarkers.
Funder
Academy of Finland
Jane ja Aatos Erkon Säätiö
Magnus Ehrnroothin Säätiö
Sigrid Juséliuksen Säätiö
Suomen kliinisen kemian yhdistys
Syöpäjärjestöt