Loss of the matriptase inhibitor HAI-2 during prostate cancer progression

Prostate cancer progression is accompanied by increased levels of extracellular proteases that are capable of remodeling the extracellular matrix as well as cleaving and activating growth factors and their receptors that are critically involved in pro-cancerous signaling pathways. The membrane anchored serine protease matriptase (also known as MT-SP1, epithin, and TADG15) has been implicated in prostate cancer. Several studies have demonstrated that the expression of this protease, both on the RNA and protein level is significantly increased during prostate cancer progression. Hepatocyte activator growth factor inhibitor-2 (HAI-2) has recently been identified as a physiological inhibitor of matriptase. It has been proposed that the increase of matriptase with a concomitant loss of its inhibitors may play a critical role in cancer progression.

In this study, we used immunohistochemistry to determine the expression of HAI-2 protein in 136 prostate cancer samples, 20 prostate benign prostatic hyperplasia (BPH) samples, and 31 normal or tumor-adjacent prostate samples. Specificity of detection was ensured by using two unrelated HAI-2 antibodies and corresponding non-immune IgG antibodies.

We demonstrate that HAI-2 protein is significantly decreased in malignant lesions as compared to normal and BPH lesions, and that the most poorly differentiated tumors (Gleason score 8-10) have the lowest level of HAI-2 expression.

These data suggest that the loss of HAI-2 may be actively involved in prostate cancer progression by causing a reduced inhibitory capacity of proteolysis possibly of the physiological target for HAI-2 matriptase.