在眾多種類的癌細胞中皆發現環氧化酶-2的過度表現，而過度表現的環氧化酶-2會催化過多前列腺素E2 的生成，而使得癌症惡化。然而，目前對於是甚麼因子導致環氧化酶-2在癌細胞中大量的表現還知之甚少。最近研究指出缺氧和發炎反應會誘導環氧化酶-2，且我們先前發現缺氧會抑制雙特異性去磷酸酶-2進而促進癌症惡化。為了瞭解雙特異性去磷酸酶-2是如何抑制腫瘤之進程，我們利用微陣列晶片大規模的篩選雙特異性去磷酸酶-2所調控的分子，我們發現環氧化酶-2是雙特異性去磷酸酶-2的下游負向調控分子之一。實驗證明當我們預先誘導雙特異性去磷酸酶-2後會顯著地降低缺氧處理、介白素-1β、表皮生長因子和前列腺素E2所誘發之環氧化酶-2的表現；另一方面，前列腺素E2會增加大腸癌病人細胞中癌症幹細胞之族群，而抑制雙特異性去磷酸酶-2後不僅會誘導環氧化酶-2的表現進而增加前列腺素E2的產生，同時會增加癌症幹細胞相關基因OCT4和SOX2的表現量。更重要的是，我們發現缺失雙特異性去磷酸酶-2所誘導之幹細胞相關基因的表現量是需要環氧化酶-2的過度表現，為了更進一步利用動物實驗探討缺失雙特異性去磷酸酶-2所造成癌症幹細胞之增加是藉由環氧化酶-2的過度表現，我們利用有限稀釋法將缺失雙特異性去磷酸酶-2或是同時缺失雙特異性去磷酸酶-2和環氧化酶-2之大腸癌細胞注入小鼠皮下。結果顯示同時缺失雙特異性去磷酸酶-2和環氧化酶-2形成異型腫瘤之能力較差且腫瘤之大小也比只有缺失雙特異性去磷酸酶-2的組別小。由於雙特異性去磷酸酶-2扮演著抑制腫瘤之重要角色，因此我們致力於尋找小分子藥物來避免雙特異性去磷酸酶-2受到缺氧所抑制；於此，我們找到兩種新穎且具有潛力的組蛋白去乙醯化酶抑制劑能夠防止雙特異性去磷酸酶-2被缺氧抑制，處理該新穎藥物不僅能夠回復缺氧所抑制之雙特異性去磷酸酶-2的表現量，更抑制缺氧所誘導之環氧化酶-2表現以及幹細胞特性；同時和已知的廣泛性組蛋白去乙醯化酶抑制劑比較後，也發現其能夠更有效地在動物模式中抑制腫瘤之生長。綜合以上之結果，我們首次發現雙特異性去磷酸酶-2抑制腫瘤惡化藉由負向調控環氧化酶-2的表現，更重要的是，我們發現兩種新穎藥物能夠防止雙特異性去磷酸酶-2被缺氧抑制，同時避免環氧化酶-2的過度表現。以上發現不僅提供我們有用之資訊且對於發展大腸癌治療之新穎策略上能夠有更新的突破。

Overexpression of cyclooxygenase-2 (COX-2) has been found in numerous types of cancers, and is associated with an increase of angiogenesis, metastasis, cancer stemness, and drug resistance via its enzymatic product, prostaglandin E2 (PGE2). However, the underlying mechanism responsible for COX-2 overexpression during cancer formation remains controversial. By analyzing DUSP2-regulated gene profiles, we identified DUSP2 reduced PGE2 synthesis by negatively controlling COX-2 expression. Results showed that pre-induction of DUSP2 using doxycycline attenuated hypoxia, IL-1β, EGF, and PGE2-induced COX-2 expression. Moreover, we found treatment with PGE2 promoted the population of CD44+CD133+ in primary colon cancer cells, which stands for cancer stem cell (CSC), and depletion of DUSP2 not only enhanced COX-2-derived PGE2 production but increased levels of stemness-related OCT4 and SOX2. More importantly, loss-of-DUSP2-induced stemness-related genes and behaviors were attenuated after combination knockdown of COX-2 and DUSP2. To further investigate whether depletion of DUSP2 induced CSC via over-production of COX-2-derived PGE2 in vivo, we performed a limited dilution assay to compare the ability of DUSP2-knockdown and COX-2-DUSP2 double knockdown cells to generate xenograft tumors. Data showed combined knockdown of DUSP2 and COX-2 not only delayed the occurrence of xenograft tumors, but also decreased shDUSP2-induced tumor size and tumor weight. Since DUSP2 is a crucial tumor suppressor, we are thus devoted to finding small molecules that prevent inhibition of DUSP2 from hypoxia. Here, we identified two potential novel histone deacetylase inhibitors (HDACIs) that protect DUSP2 from suppression by hypoxia, while preventing hypoxia-induced COX-2 expression. Treatment with novel HDAC occurs under hypoxia-disrupted hypoxia-induced stemness behavior and drug-resistance in vitro, and also efficiently limited xenograft tumor growth as compared with a known pan-HDACi, SAHA. Taken together, we demonstrated that DUSP2 negatively regulates cancer malignancy via inhibition of COX-2; more importantly, we identified potential anti-cancer compounds that prevent downregulation of DUSP2, as well as induction of COX-2, by hypoxia. These findings provide useful information and new directions for designing therapeutic treatments for colon cancer patients.

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