探討亞型環氧化酶在攝護腺癌細胞的侵襲以及間質蛋白酶活化的影響

Role of Cyclooxygenase-2 in prostate cancer cell invasion and modulating matriptase activity.

賴碧芳(Pee-Fang Lai)

指導教授 ： 李明學

國立臺灣大學/醫學院/生物化學暨分子生物學研究所/碩士(2013年)

https://doi.org/10.6342/NTU.2013.10517

摘要

近年來在台灣，攝護腺癌的發生率以及死亡率有逐年增加的趨勢。有些研究指出慢性發炎與攝護腺癌的早期發生以及惡化有關。亞型環氧化酶 (Cyclooxygenase-2, COX-2) 是一種花生四烯酸 (arachidonic acid, AA) 代謝過程中合成前列腺素 (prostaglandins, PGs) 的限速酶，近年研究指出亞型環氧化酶在一些癌症，如大腸癌，乳癌，肺癌以及攝護腺癌具有高度表達的現象。然而，亞型環氧化酶是否參與攝護腺癌細胞侵襲的分子機制尚未了解。在本篇研究裡，我建立了在攝護腺癌細胞PC-3高度表現亞型環氧化酶以及抑制亞型環氧化酶表現量的細胞模式，進而探討攝護腺癌細胞的侵襲能力。結果發現大量表現亞型環氧化酶增加了攝護腺癌細胞PC-3的侵襲能力以及第二型嵌膜絲胺酸蛋白酶間質蛋白酶(Matriptase)的活化。相反地，抑制亞型環氧化酶的表現量亦降低了攝護腺癌細胞的侵襲能力，同時抑制了間質蛋白酶的活化程度。為了更進一步研究亞型環氧化酶在攝護腺癌細胞中扮演的角色，我發現亞型環氧化酶的主要產物前列腺素E2 (PGE2) 可促進攝護腺癌細胞的侵襲能力及刺激間質蛋白酶的活化。實驗結果指出PGE2刺激間質蛋白酶活化的分子機制可能是透過AKT訊息傳遞。另外，本篇實驗結果也指出，在一些抑制亞型環氧化酶及非類固醇抗炎藥物 (NSAIDs) 中，希樂葆 (Celebrex) 和硫化舒磷酸 (Sulindac Sulfide) 可有效地抑制攝護腺癌細胞的移動與侵襲能力以及降低間質蛋白酶的活化。整體來說，亞型環氧化酶的表現量可能藉由影響間質蛋白酶的活化來調控攝護腺癌細胞的侵襲能力。因此探討亞型環氧化酶是未來一個具有潛力的課題，藉由抑制此酵素也許是一個有效的策略，進而降低攝護腺癌的惡化。

關鍵字

攝護腺癌 ； 亞型環氧化酶第二型嵌膜絲胺酸蛋白酶前列腺素

並列摘要

The recent incidence of prostate cancer (PCa) is annually rising in Taiwan. Chronic inflammation has been revealed to contribute to the early development and progression of PCa. Several studies have indicated that cyclooxygenase-2 (COX-2), a key enzyme to generate prostaglandins during inflammation is commonly overexpressed in human cancers including PCa, and correlated with PCa progression. However, the molecular mechanism how COX-2 promotes PCa cell invasion is not well understood. In this study, we investigated the role of COX-2 in PCa cell invasion and delineated the molecular mechanism in which COX-2 signaling involved in PCa cell invasion. Using overexpression and knockdown approaches. the results showed that COX-2 overexpression could enhance PCa PC3 cell invasion, partly due to up-regulating matriptase, while COX-2 knockdown resulted in decreasing the cancer cell invasion, and the activated level of matriptase. Moreover, PGE2, the major prostaglandin of COX-2, was able to induce PCa cell invasion and matriptase activation. With NSAIDs, the data showed that sulindac sulfide and celebrex exhibited significant effects on suppressing PCa cell invasion and down-regulating matriptase. Taken together, the data indicate that COX-2 is involved in promoting PCa cell invasion, at least in part due to increasing matriptase activation, suggesting that suppression of COX-2 signaling may be a strategy to reduce PCa progression.

並列關鍵字

prostate cancer ； cyclooxygenase-2 ； matriptase ； PGE2

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