第二型嵌膜絲胺酸蛋白酶II在攝護腺癌症進程及轉移所扮演的角色

Abstract

在攝護腺癌的進程中，雄性激素的訊息傳遞及細胞周圍的蛋白水解現象常會失去良好的調控，然而其所扮演的角色及其間的相互關係，仍尚未完全清楚。在此研究中，發現第二型嵌膜絲胺酸蛋白酶II (TMPRSS2) 可誘發一組蛋白水解傳遞鏈，進而調控雄性激素所引起的攝護腺癌細胞侵襲、腫瘤生長及轉移的現象。在攝護腺癌中，我的研究鑑識出間質蛋白酶 (matriptase) 是第二型嵌膜絲胺酸蛋白酶 II的受質並參與由雄性激素所促進的癌細胞侵襲行為。在攝護腺癌組織中，我進一步地使用組織染色，經統計分析，其結果指出較高的第二型嵌膜絲胺酸蛋白酶 II表達量與間質蛋白酶的高度活化有明顯的相關性。最後，利用小鼠腫瘤研究模式，我發現第二型嵌膜絲胺酸蛋白酶 II 可促進攝護腺癌腫瘤生長及轉移能力，此結果與第二型嵌膜絲胺酸蛋白酶 II增進間質蛋白酶的活性及降解細胞外基質 nidogen-1 和 laminin beta-1有顯著的關聯性。我們進一步地鑑定了第二型嵌膜絲胺酸蛋白酶 II內生性的蛋白抑制分子，可以有效地抑制第二型嵌膜絲胺酸蛋白酶 II的活性及其所導致的細胞侵襲。 綜合以上研究顯示第二型嵌膜絲胺酸蛋白酶 II 經由促進間質蛋白酶的活化及細胞外基質的降解，進而促進攝護腺癌細胞的侵襲、腫瘤生長及轉移。這些成果提供在研究攝護腺癌治療的未來發展策略，將可利用第二型嵌膜絲胺酸蛋白酶 II 及間質蛋白酶作為治療標把，進而抑制攝護腺腫瘤生長與轉移。

Dysregulation of androgen signaling and pericellular proteolysis are necessary for prostate cancer progression but the links between them are still obscure. In this study, we show how the membrane-anchored serine protease TMPRSS2 stimulates a proteolytic cascade that mediates androgen-induced prostate cancer cell invasion, tumor growth and metastasis. We found that matriptase served as a substrate for TMPRSS2 in mediating this pro-invasive action of androgens in prostate cancer. In prostate cancer tissues, higher levels of TMPRSS2 expression correlated with higher levels of matriptase activation. The ability of TMPRSS2 to promote prostate tumor growth and metastasis was associated with increased matriptase activation and enhanced degradation of extracellular matrix nidogen-1 and laminin beta-1 in tumor xenografts. Furthermore, we also identified the endogenous serine protease inhibitors which efficiently inhibit TMPRSS2 activity and TMPRSS2-induced cell invasion. In summary, our results establish that TMPRSS2 promotes the growth, invasion and metastasis of prostate cancer cells via matriptase activation and extracellular matrix disruption, with implications to target these two proteases as a strategy to treat prostate cancer.