Proteases have been implicated in the
tumorigenesis and aggressiveness of a variety of
cancer types. In fact,
proteases have proven to be very clinically useful as
tumor biomarkers in the blood of patients.
Proteases are typically involved in complex systems of substrates, activators, and inhibitors, thus making our ability to establish their exact function in
cancer more difficult.
Trypsin, perhaps the most famous of
proteases, has been shown to play a role in
cancer progression, but its functional role in
ovarian cancer has not been much studied. PAR2, a transmembrane receptor that is known to be activated by
trypsin, has been reported to be associated with
ovarian cancer. Here, we found that stimulation of
ovarian cancer cell lines with
trypsin or PAR2 activating
peptide markedly increased MAPK signaling and cell proliferation. Additionally, HE4, a WAP-family
glycoprotein and
ovarian cancer biomarker, was found to inhibit
trypsin degradation, thereby retaining its activity. Patient data seemed to support this phenomenon, as the serum of
ovarian cancer patients with high HE4 expression, revealed significantly elevated
trypsin levels. These data support the hypothesis that
trypsin plays a tumorigenic role in
ovarian cancer, which can be mediated by its
receptor PAR2, and potentiated by HE4.