Cyclooxygenase-1 is overexpressed in multiple genetically engineered mouse models of epithelial ovarian cancer
Cyclooxygenase-1 is overexpressed in multiple genetically engineered mouse models of epithelial ovarian cancer
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DOI：
10.1158/0008-5472.can-05-4063
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Dey, SK
中科院分区：
文献类型：
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作者：
Daikoku, T;Tranguch, S;Dey, SK
环氧合酶-1和环氧合酶-2(COX-1和COX-2)是催化花生四烯酸转化为前列腺素的两种不同的亚型。环氧合酶-2在多种癌症中的作用已被公认，但环氧合酶-1的作用仍很少被研究。我们先前已经表明，人类上皮性卵巢肿瘤中COX-1的水平升高，但COX-2的水平没有升高。我们还观察到COX-1在上皮性卵巢癌(EOC)小鼠模型中高表达，该模型缺乏P53，但过表达c-myc和K-ras或c-myc和Akt。更重要的是，COX-1选择性抑制剂SC-560抑制EOC生长。在目前的研究中，我们使用了不同的卵巢癌基因工程小鼠模型来确定COX-1的过度表达是特定的遗传和致癌改变所独有的，还是普遍存在的。这些模型包括：(A)P53和Rb的缺失，(B)在苗勒氏抑制物质II型受体的控制下诱导SV40的转化区，或(C)在卵巢表面上皮细胞中局部缺乏Pten的情况下K-RAS的激活。我们发现，这三种产生自发卵巢的模型也显示出COX-1的表达上调，但没有COX-2的表达。这些结果进一步证明COX-1在不同的卵巢癌模型中普遍过表达。因此，COX-1可作为卵巢上皮性癌的潜在标志物，并有可能成为预防和/或治疗这一致命疾病的靶点。
Cyclooxygenases-1 and -2 (Cox-1 and Cox-2) are two distinct isoforms that catalyze the conversion of arachidonic acid to prostaglandins. The role of Cox-2 in a variety of cancers is well recognized, but the contribution of Cox-1 remains much less explored. We have previously shown that human epithelial ovarian tumors have increased levels of Cox-1, but not Cox-2. We also observed that Cox-1 is highly expressed in a mouse model of epithelial ovarian cancer (EOC), which lacks p53 but overexpresses c-myc and K-ras or c-myc and Akt. More importantly, a Cox-1-selective inhibitor, SC-560, attenuates EOC growth. In the present investigation, we used various genetically engineered mouse models of EOC to determine whether Cox-1 overexpression is unique to specific genetic and oncogenic alterations or is widespread. These models include: (a) deletion of both p53 and Rb, (b) induction of the transforming region of SV40 under the control of Mullerian inhibitory substance type II receptor, or (c) activation of K-Ras in the absence of Pten locally in the ovarian surface epithelium. We found that these three models, which produce spontaneous EOC, also show up-regulated expression of Cox-1, but not Cox-2. The results provide further evidence that Cox-1 overexpression is common in various models of EOC. Thus, Cox-1 serves as a potential marker of EOC and is a possible target for the prevention and/or treatment of this deadly disease.