利用抑制ADAM9的存活訊息增進放射線療法對於攝護腺癌的抗腫瘤效應; Inhibition of ADAM9 survival signals enhances anti-tumor effect of radiotherapy in prostate cancer

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题名:	利用抑制ADAM9的存活訊息增進放射線療法對於攝護腺癌的抗腫瘤效應;Inhibition of ADAM9 survival signals enhances anti-tumor effect of radiotherapy in prostate cancer
作者:	羅聖傑;Sheng-Jie Luo
贡献者:	中國醫藥大學：癌症生物學研究所
关键词:	攝護腺癌;prostate cancer
日期:	2009-07-03
上传时间:	2009-08-12 13:50:03 (UTC+8)
摘要:	研究背景: ADAM (A disintegrin and metalloprotease) 是一群具有多種生物功能的蛋白質家族。當我們利用組織晶片(tissue array)分析發現ADAM9在攝護腺癌的病人檢體中有增加的趨勢，而且將攝護腺癌細胞株培養於壓力的條件下(缺氧和細胞擁塞)會誘導ADAM9的表現，或在越趨惡化之同源攝護腺癌細胞株中ADAM9也會有正向的增加趨勢。更進一步研究證實ADAM9是透過活性氧(reactive oxygen species， ROS)當成一個中介者(mediator)進而被誘導表現。此外，之前的研究也發現ADAM9在androgen dependent的攝護腺癌細胞中會受到雄性激素(androgen)的調控進而被誘導表現，但是在androgen independent的攝護腺癌細胞中，ADAM9則不受雄性激素(androgen)的調控。因此，根據上述的研究得知ADAM9是一種抗逆境蛋白(stress responsive protein)，對於攝護腺癌在壓力的條件下對抗細胞凋亡的過程中扮演一個重要的角色。所以我們提出假說，利用knockdown ADAM9合併放射線療法可以大幅的增加放射線療法對於攝護腺癌治療的有效性。在本研究中，我們把焦點放在探討ADAM9的生物活性對於androgen independent的攝護腺癌之進程發展。材料方法: 為了探討ADAM9在攝護腺癌的進程發展中扮演的角色，我們研究比較在PC3 細胞株中轉殖ADAM9 siRNA (PC3ADAM9siRNA)或vector control (PC3controlsiRNA)對於PC3細胞株之遷移能力(migration)、侵襲能力(invasion)、增殖能力(proliferation)的影響。在活體實驗 (in vivo)中，我們先利用luciferase-tagged PC3ADAM9siRNA 或 PC3controlsiRNA，之後利用皮下注射(s.c)或脛骨注射(tibia injection)的方式來探討PC3ADAM9siRNA 或 PC3controlsiRNA對於腫瘤的生長之影響。結果: 我們利用foci formation實驗證明knockdown ADAM9之後會降低攝護腺癌細胞PC3的colonies的大小，另外我們也證明了當Knockdown ADAM9之後會降低攝護腺癌細胞PC3的遷移能力(migration)以及侵襲能力(invasion)，最後在in vivo中我們也從裸鼠的皮下注射(s.c)和脛骨注射(tibia injection)的實驗裡證明了knockdown ADAM9的攝護腺癌細胞PC3株(PC3ADAM9siRNA)會顯著的降低其腫瘤生成的能力。總結上述的研究，我們證明knockdown ADAM9的表現可以大幅的降低護腺癌的進程發展，以及ADAM9有潛力可以應用在攝護腺癌的標靶治療上。 Introduction: The family of a disintegrin and metalloprotease (ADAM) consists of over 30 members displaying multiple biological functions. Previously tissue array analyses confirmed the increasing of ADAM9 correlated with prostate cancer progression. Several studies demonstrated that stresses, including hypoxia and cell crowding, induced ADAM9 elevation during cancer progression. We further confirmed the ADAM9 expression is driven by the production of reactive oxygen species (ROS). In addition, androgen could induce ADAM9 expression in androgen-dependent but not androgen-independent prostate cancer cells, suggesting a possible role of androgen in regulating ADAM9 expression. ADAM9 is known to play an important role in anti-apoptosis in prostate cancer cells in response to stress condition and androgen regulation. Hence, we hypothesize that knockdown of ADAM9 expression may greatly enhance the efficacy of radiotherapy. In this report, we focus on the studies of biological activity of ADAM9 in androgen-independent prostate cancer progression in the in vitro and in vivo models Materials and methods: To evaluate the role of ADAM9 in prostate cancer progression, we examined and compared the ability of cell migration, invasion, and proliferation between ADAM9 siRNA-transfected PC3 (PC3ADAM9siRNA) and its vector control (PC3controlsiRNA) cell lines in vitro. For in vivo assay, luciferase-tagged PC3ADAM9siRNA and PC3controlsiRNA cells were injected into the subcutaneous and tibia of nude mice. Tumor growth was determined and compared by caliper and/or bioluminescence image. Results and conclusion: We found the decreases of colony number and size after knockdown of ADAM9 expression in PC3 cells in the foci formation studies. The cell migration was significantly reduced by knocking down ADAM9 in androgen-independent prostate cancer PC3 cell line. The growth of PC3ADAM9siRNA showed significant decreases compared to PC3cotrnolsiRNA in both subcutaneous tissue and bone. In conclusion, our finding demonstrated that knockdown of ADAM9 expression greatly reduce prostate cancer progression and may be used for anti-prostate cancer therapy.
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