Dysregulation of cell surface proteolysis has been strongly implicated in tumorigenicity and
metastasis. In this study, we delineated the role of
hepatocyte growth factor activator inhibitor-2 (HAI-2) in
prostate cancer (PCa) cell migration, invasion, tumorigenicity and
metastasis using a human PCa progression model (103E, N1, and N2 cells) and xenograft models. N1 and N2 cells were established through serial intraprostatic propagation of 103E human PCa cells and isolation of the metastatic cells from nearby lymph nodes. The invasion capability of these cells was revealed to gradually increase throughout the serial isolations (103E<N1<N2). In this series of cells, the expression of HAI-2 but not HAI-1 was significantly decreased throughout the progression and occurred in parallel with increased activation of
matriptase. The expression level and activity of
matriptase increased whereas the HAI-2
protein level decreased over the course of orthotopic
tumor growth in mice, which was consistent with the immunohistochemical profiles of
matriptase and HAI-2 in archival PCa specimens. Knockdown of
matriptase reduced the PCa cell invasion induced by HAI-2 knockdown. HAI-2 overexpression or
matriptase silencing in N2 cells downregulated
matriptase activity and significantly decreased tumorigenicity and metastatic capability in orthotopically xenografted mice. These results suggest that during the progression of human PCa,
matriptase activity is primarily controlled by HAI-2 expression. The imbalance between HAI-2 and
matriptase expression led to
matriptase activation, thereby increasing cell migration, invasion, tumorigenicity and
metastasis.