摘要:攝護腺癌 在西方國 家中是最被常診斷出 的男性 癌症。 目前 攝護腺癌是台灣男性 第七 位死 亡病因且致病率 持續快速上升中。 在攝護腺癌 惡化 過程中, 癌細胞經常轉變成對男性 賀 爾蒙 非依賴型並同時 獲得較高的生長,移動與侵襲能力,造成預後 效果較差。第二型嵌 。第二型嵌 膜蛋白 酶(TMPRSS2) 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 是一種可受男性賀爾蒙誘發表現的蛋白酶。先前研究報告指出在惡 性的攝護腺癌細 胞中,此蛋白酶會大量表現並從細膜移至質。另一方面也有報 胞中,此蛋白酶會大量表現並從細膜移至質。另一方面也有報 胞中,此蛋白酶會大量表現並從細膜移至質。另一方面也有報 胞中,此蛋白酶會大量表現並從細膜移至質。另一方面也有報 胞中,此蛋白酶會大量表現並從細膜移至質。另一方面也有報 告指出,在轉移至骨骼的男性賀爾蒙非依賴型攝護腺癌細胞中, TMPRSS2 的表現量會下 降。 因此, TMPRSS2 的表現或活性關聯著癌症生成,病情進展轉移。為了一步瞭解 TMPRSS2 在男性賀爾蒙所調控的蛋白酶疊層及其攝護腺癌惡化過程中扮演角色, 我們 使用此蛋白酶膜外區塊 製備 專一 單株抗體 。利用 此抗體, 我們 發現男性賀爾蒙可以 發現男性賀爾蒙可以 誘使攝護腺癌細胞移動與轉以及 TMPRSS2 表現和間質蛋白酶活化。退除 TMPRSS2 後, 此賀爾蒙失去 對間質蛋白酶活化的效用。單獨大量表現 間質蛋白酶活化的效用。單獨大量表現 間質蛋白酶活化的效用。單獨大量表現 間質蛋白酶活化的效用。單獨大量表現 TMPRSS2 也可促進間質蛋白酶活 化。同時, 利用 兩組 攝護腺癌 攝護腺癌 攝護腺癌 細胞 進化 模式 (攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 攝護腺癌侵襲轉移細胞膜式; 男性賀爾蒙 依 賴型與非依 賴型與非依 賴型與非依 賴型與非依 賴型與非依 賴型與非賴型細胞模式 賴型細胞模式 賴型細胞模式 賴型細胞模式 賴型細胞模式 賴型細胞模式 ),我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, , 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞, 我們發現具高轉移性或男賀爾蒙非依賴型癌細胞TMPRSS2 表現 量下降。大TMPRSS2 會抑制攝護腺 DU 145 癌細胞移動與侵襲。退除 TMPRSS2 的表現,促進細胞生長速率。因此我們假設 TMPRSS2 參與男性賀爾蒙誘發間質 參與男性賀爾蒙誘發間質 蛋白酶活化的疊層且降低 TMPRSS2 表現會促進攝護腺癌的生長,移動侵襲腫瘤形成 表現會促進攝護腺癌的生長,移動侵襲腫瘤形成 表現會促進攝護腺癌的生長,移動侵襲腫瘤形成 表現會促進攝護腺癌的生長,移動侵襲腫瘤形成 表現會促進攝護腺癌的生長,移動侵襲腫瘤形成 表現會促進攝護腺癌的生長,移動侵襲腫瘤形成 表現會促進攝護腺癌的生長,移動侵襲腫瘤形成 與轉移。此計劃主要探討分析 與轉移。此計劃主要探討分析 與轉移。此計劃主要探討分析 (1) TMPRSS2 在男性賀爾蒙誘發間質蛋白 酶活化所扮演的角 色, (2) TMPRSS2 對攝護腺癌細胞生長, 移動與侵襲能力的影響(3) TMPRSS2 對攝護腺 癌腫瘤生成與轉移的影響, 癌腫瘤生成與轉移的影響, (4)找尋 TMPRSS2 的受質, 的受質, (5)偵測 TMPRSS2 在攝護腺癌病人 組織的表現量與分布。本計劃成果將有助於我們更瞭解 組織的表現量與分布。本計劃成果將有助於我們更瞭解 組織的表現量與分布。本計劃成果將有助於我們更瞭解 TMPRSS2 在男性賀爾蒙作用下 調控間質蛋白 酶的分子機制。並提供資料解釋攝護腺癌為何在 TMPRSS2 表現下降情況, 讓癌細胞惡化及對正常組織侵襲。這些研究成果將有助於發展新的效醫療方式來避免 讓癌細胞惡化及對正常組織侵襲。這些研究成果將有助於發展新的效醫療方式來避免 讓癌細胞惡化及對正常組織侵襲。這些研究成果將有助於發展新的效醫療方式來避免 讓癌細胞惡化及對正常組織侵襲。這些研究成果將有助於發展新的效醫療方式來避免 或
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During the prostate cancer progression, cancer cells often transform from androgen dependence to independence, that often acquires high cell proliferation, migration and invasion, leading to poor prognosis. Recently, membrane-anchored serine proteases have been reported to play roles in cancer cell migration and invasion due to their aberrant proteolytic activities to break down extracellular matrixs. Type II transmembrane protease, serine 2 (TMPRSS2) is an androgen-regulated gene which encodes a protease with a trypsin-like proteolytic activity. It has been reported that TMPRSS2 is preferentially expressed in normal prostate tissues, and highly expressed with a shift of subcellular localization from plasma membrane to cytoplasm in advanced prostate cancer. Moreover, it has been also shown that the expression of TMPRSS2 is down-regulated in androgen-independent prostate cancer xenograft tissue from a bone metastasis. Based on these studies, TMPRSS2 may exhibit roles in prostate cancer progression and metastasis. To further explore the roles of TMPRSS2 in androgen-induced proteolytic cascade and in the progression of prostate cancer, we generated a high affinity monoclonal antibody specific to TMPRSS2 and will employ this antibody for the study. Our preliminary data showed that androgens could promote prostate cancer cell migration and invasion, which were concurrent with induction of TMPRSS2 expression and the activation of matriptase. With TMPRSS2 knockdown, androgens reduced its stimulatory effect on matriptase. Within two prostate cancer progression models: Model 1 includes 103E, N1 and N2 cells with increased cancer cell invasion by serial orthotopic selections; Model 2 represents a progression model from an androgen-sensitive to androgen-independent stage including C-33 and C-81 LNCaP cells, the expression of TMPRSS2 was decreased in the cells having highly invasive, tumorigenic or androgen-independent phenotypes. TMPRSS2 overexpression could inhibit the migration of prostate cancer DU145 cells. Knockdown of TMPRSS2 in C-33 LNCaP cells could enhance cell proliferation. Thus, TMPRSS2 may play a negative role in the prostate cancer progression. Our hypothesis is that TMPRSS2 plays roles in an androgen-induced proteolytic cascade for matriptase activation and a decrease of TMPRSS2 expression results in promoting prostate cancer cell proliferation, migration, invasion, tumorigenicity and metastasis. To test this hypothesis, the following experiments will be carried out: 1) To address the role of TMPRSS2 in androgen-induced matriptase activation and prostate cancer cell migration and invasion, 2) To analyze the role of TMPRSS2 in the progression of prostate cancer cells, 3) To examine the role of TMPRSS2 in tumorigenicity and metastasis of prostate cancer, 4) To identify the in vivo substrates or interacting proteins of TMPRSS2 in prostate cancer cells, 5) To analyze the expression levels of TMPRSS2 in archival specimens of prostate cancer patients. The results of these experiments will help us to understand the molecular mechanism in which TMPRSS2 plays roles in androgen-induced proteolytic cascades and prostate cancer progression. The information generated from the study may be useful for developing a novel strategy for prostate cancer therapy.