Kallikrein-related peptidase 7 induces pro-angiogenic signals in ovarian cancer

L Silva1, T Stoll2, C Stephens1, M Hastie2, Y Dong1, O Kleifeld3, J Gorman2 and J Clements1

  1. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD
  2. QIMR Berghofer Institute of Medical Research, Brisbane, QLD
  3. Monash Biomedical Proteomic Facility, Monash University, Clayton, VIC

Proteases are key regulators of cell signalling, and thus ideal therapeutic targets. Kallikrein-related peptidase 7 (KLK7) is a serine protease that is aberrantly expressed in ovarian cancer cells where it has been shown to enhance cell migration, invasion and resistance to chemotherapy, three of the hallmarks of cancer progression. However, to target KLK7 action in ovarian cancer as a potential therapy, the underlying mechanism of action must be elucidated. We have used proteomic and transcriptomic (RNA-Seq) approaches to identify KLK7 substrates and indirectly regulated gene targets to understand the KLK7-mediated signalling pathways in ovarian cancer. Results were further validated by biochemical approaches and qRT-PCR. Functional validations were performed using cell proliferation assays (IncuCyte ZOOM® and CyQUANT).We identified 15 substrates, with high confidence, reflecting the mechanisms underlying known KLK7 cancer promoting functions. Intriguingly, some KLK7-mediated cleavage events were detected to produce pro-angiogenic signals. Moreover, KLK7-mediated indirect gene regulation also demonstrated activation of three angiogenesis-related signalling pathways, including the VEGF signalling pathway, suggesting a novel putative functional role for KLK7. These results were further validated by biochemical and functional assays. With its established pro-tumorigenic autocrine effects, coupled to its putative novel role identified herein as a mediator of angiogenesis, KLK7 is a promising therapeutic target in ovarian cancer therapy. KLK7-mediated proteolysis potentially could be inhibited clinically to influence optimal disease regression, through interrupting pro-tumorigenic signals from the tumour.