探討攝護腺蛋白酶在攝護腺癌發展中扮演的角色

Abstract

攝護腺蛋白酶 (Prostasin) 屬於多醣磷脂肌醇錨定 (glycosylphosphatidylinositol (GPI)-anchored) 的絲胺酸蛋白酶，能夠與間質蛋白酶 (matriptase) 共同調控表皮細胞的發育以及恆定。但是目前還不清楚prostasin在人類攝護腺癌上扮演的角色。在我的研究當中，我致力探討prostasin是否調控攝護腺癌的侵襲能力，並且釐清是透過甚麼分子機制。結果顯示在攝護腺癌上過度表達prostasin能夠抑制癌細胞的侵襲能力，相反的如果抑制 prostasin的表達，則會促進癌細胞的侵襲。深入探討發現，prostasin切割未活化matriptase的位點並非在第614號的精氨酸，這個結果顯示matriptase在受prostasin調控後，在生理上或病理上可能會有不同的功能。更進一步發現 prostasin能夠透過促進細胞膜上的matriptase釋放到細胞外的，降低細胞內matriptase的蛋白量。除此之外，我也發現prostasin能夠抑制雄激素 (androgens) 所引導促進的攝護腺癌LNCaP細胞的侵襲，顯示prostasin在雄激素的訊息傳導當中，也扮演負向調控者的角色。總結來說，這些研究結果顯示prostasin具有抑制攝護腺癌細胞發展的能力，並且對抗雄激素所促進的攝護腺癌細胞侵襲。

Prostasin is a glycosylphosphatidylinositol (GPI)-anchored serine protease and plays a pivotal role in the development and homeostasis of normal epithelial cells. However, the role of prostasin in human prostate cancer is still unclear. In this study, I investigated to elucidate the role of prostasin in prostate cancer cell invasion, and the molecular mechanism how prostasin exhibited its role in prostate cancer cells. The results showed that overexpression of prostasin reduced prostate cancer cell invasion, while prostasin silencing enhanced prostate cancer cell motility. Moreover, I found that prostasin cleaves matriptase zymogen at an unknown site rather than the R614 residue of matriptase which imply prostasin has distinct regulation on matriptase physiologically or pathologically. Further, prostasin decreases the cellular protein levels of matriptase by promoting matriptase shedding into the conditioned media. These results indicate prostasin moderates matriptase to suppress cancer cell invasion. In addition, prostasin was able to inhibit androgen-induced prostate cancer LNCaP cell invasion, indicating prostasin also plays as a negative regulator in androgen signaling. In summary, the results together indicate that prostasin functions as a suppressor for human prostate cancer cells and can conquer androgen-induced prostate cancer cell invasion.