The Wilmot Cancer Institute at the University of Rochester Medical Center, Rochester, NY, United States of America.
PLoS One. 2020 May 4;15(5):e0232253. doi: 10.1371/journal.pone.0232253. eCollection 2020.
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.
蛋白酶参与了多种癌症类型的肿瘤发生和侵袭。事实上，蛋白酶已被证明在患者血液中的肿瘤标志物方面具有非常实际的应用价值。蛋白酶通常涉及到底物、激活剂和抑制剂的复杂系统，因此我们更难确定它们在癌症中的确切功能。胰蛋白酶，也许是最著名的蛋白酶之一，已被证明在癌症进展中发挥作用，但它在卵巢癌中的功能作用尚未得到广泛研究。PAR2 是一种已知被胰蛋白酶激活的跨膜受体，据报道与卵巢癌有关。在这里，我们发现用胰蛋白酶或 PAR2 激活肽刺激卵巢癌细胞系会显著增加 MAPK 信号和细胞增殖。此外，HE4，一种 WAP 家族糖蛋白和卵巢癌生物标志物，被发现抑制胰蛋白酶的降解，从而保留其活性。患者数据似乎支持这一现象，因为高 HE4 表达的卵巢癌患者的血清中，明显升高了胰蛋白酶水平。这些数据支持胰蛋白酶在卵巢癌中发挥致癌作用的假设，这可以通过其受体 PAR2 介导，并通过 HE4 增强。
