鑑選抑制第二型絲胺酸蛋白酶所誘發攝護腺癌細胞侵襲的調控蛋白

攝護腺癌的惡化進程是一個多步驟且複雜的過程。一旦攝護腺癌發生轉移，治癒癌症將變得很困難。癌轉移機制目前尚未完全清楚，但轉移的過程中，細胞周圍蛋白酶水解作用扮演相當重要的角色。最新研究指出第二型嵌膜絲胺酸蛋白酶II (TMPRSS2) 參與攝護腺癌細胞侵襲及轉移;其機制經由活化受質間質蛋白酶 (matriptase)及細胞間質的降解，造成攝護腺癌細胞侵襲力增加、腫瘤生長及轉移。因生理上蛋白酶均會受到蛋白酶抑制蛋白的調控，本篇研究將進一步鑑尋TMPRSS2抑制蛋白。利用免疫沉澱及質譜分析的方式，其結果發現許多可與第二型嵌膜絲胺酸蛋白酶II作用的候選蛋白質，其中具有Kunitz domain的第一型和第二型肝細胞生長因子活化抑制者(HAI-1 HAI-2)最引起我們的研究興趣。經由生化分析重組的第二型肝細胞生長因子活化抑制者(HAI-2)蛋白質相較於第一型肝細胞生長因子活化抑制者(HAI-1)，對TMPRSS2有較顯著的活性抑制效果。進一步發現第二型肝細胞生長因子活化抑制者的Kunitz domain 2是與TMPRSS2交互作用的重要區塊。再者，在攝護腺癌細胞中表達第二型肝細胞生長因子活化抑制者，可以降低由第二型嵌膜絲胺酸蛋白酶II所引發的腫瘤細胞侵襲能力，證實第二型嵌膜絲胺酸蛋白酶II確實可受到第二型肝細胞生長因子活化抑制者的抑制調控。這些研究提供未來攝護腺癌治療的新策略方向，可利用調節第二型嵌膜絲胺酸蛋白酶 II 及第二型肝細胞生長因子活化抑制者兩者間的平衡，達到抑制攝護腺腫瘤生長與轉移的目的。

關鍵字

第二型嵌膜絲胺酸蛋白? II ；第一型肝細胞生長因子活化抑制者；第二型肝細胞生長因子活化抑制者；間質蛋白? ；攝護腺癌；轉移

並列摘要

Dysregulation of pericellular serine proteases has been proposed as an important effector for tumor progression, because of their roles in the degradation of extracellular matrix and alteration of microenvironment for invasive tumor growth. Among them, TMPRSS2, a type II serine protease acts as an important mediator in androgen-induced prostate cancer cell invasion, tumor growth and metastasis, via a proteolytic activation of matriptase and degradation of extracellular matrix. For a proteolytic system, there is a general phenomenon that proteases are usually accompanied with their cognate protease inhibitors via non-covalent interaction. To further identify whether there is a serine protease inhibitor to modulate the activity of TMPRSS2, in this study, we used co-immunoprecipitation assay and LC/MS/MS analysis to isolate TMPRSS2-interacting proteins, and isolated the candidates of hepatocyte growth factor activator inhibitors (HAIs) as an inhibitor for TMPRSS2. The recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1. Moreover, the results from co-immunoprecipitation showed that HAI-2 could form a complex with TMPRSS2. HAI-2 overexpression could suppress TMPRSS2-induced prostate cancer cell invasion. In summary, the results indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in prostate cancer cells.

並列關鍵字

TMPRSS2 ； HAI-1 ； HAI-2 ； matriptase ； prostate cancer ； metastasis

參考文獻

[1] Chen YW, Lee MS, Lucht A, Chou FP, Huang W, Havighurst TC, Kim K, Wang JK, Antalis TM, Johnson MD, Lin CY: TMPRSS2, a serine protease expressed in the prostate on the apical surface of luminal epithelial cells and released into semen in prostasomes, is misregulated in prostate cancer cells. Am J Pathol 2010, 176:2986-96.