Prostate-specific antigen (PSA) and the related
kallikrein family of
serine proteases are current or emerging
biomarkers for
prostate cancer detection and progression.
Kallikrein 4 (KLK4/hK4) is of particular interest, as KLK4
mRNA has been shown to be elevated in
prostate cancer. In this study, we now show that the comparative expression of hK4
protein in
prostate cancer tissues, compared with benign glands, is greater than that of PSA and
kallikrein 2 (KLK2/hK2), suggesting that hK4 may play an important functional role in
prostate cancer progression in addition to its
biomarker potential. To examine the roles that hK4, as well as PSA and hK2, play in processes associated with progression, these
kallikreins were separately transfected into the PC-3
prostate cancer cell line, and the consequence of their stable transfection was investigated. PC-3 cells expressing hK4 had a decreased growth rate, but no changes in cell proliferation were observed in the cells expressing PSA or hK2. hK4 and PSA, but not hK2, induced a 2.4-fold and 1.7-fold respective increase, in cellular migration, but not invasion, through
Matrigel, a synthetic extracellular matrix. We hypothesised that this increase in motility displayed by the hK4 and PSA-expressing PC-3 cells may be related to the observed change in structure in these cells from a typical rounded epithelial-like cell to a spindle-shaped, more mesenchymal-like cell, with compromised adhesion to the culture surface. Thus, the expression of
E-cadherin and
vimentin, both associated with an epithelial-mesenchymal transition (EMT), was investigated.
E-cadherin protein was lost and
mRNA levels were significantly decreased in PC-3 cells expressing hK4 and PSA (10-fold and 7-fold respectively), suggesting transcriptional repression of
E-cadherin, while the expression of
vimentin was increased in these cells. The loss of
E-cadherin and associated increase in
vimentin are indicative of EMT and provides compelling evidence that hK4, in particular, and PSA have a functional role in the progression of
prostate cancer through their promotion of tumour cell migration.