Elevated cyclooxygenase-2 expression is associated with altered expression of p53 and SMAD4, amplification of HER-2/neu, and poor outcome in serous ovarian carcinoma
Elevated cyclooxygenase-2 expression is associated with altered expression of p53 and SMAD4, amplification of HER-2/neu, and poor outcome in serous ovarian carcinoma
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DOI：
10.1158/1078-0432.ccr-0132-03
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发表时间：
2004-01-15
影响因子：
11.5
通讯作者：
Ristimäki, A
中科院分区：
文献类型：
--
作者：
Erkinheimo, TL;Lassus, H;Ristimäki, A
目的和实验设计：环氧合酶-2(COX-2)在人类腺癌中频繁表达，抑制COX-2可抑制各种致癌动物模型中肿瘤的形成。应用免疫组织化学方法(n=442)、Western blotting(n=12)和逆转录聚合酶链式反应(n=12)检测COX-2蛋白在卵巢浆液性癌中的表达。结果：逆转录聚合酶链式反应和Western印迹分析分别检测到75%(9/12)和42%(5/12)的浆液性卵巢癌组织中COX-2mRNA和COX-2蛋白的表达。在442例肿瘤中，有310例(70%)COX-2呈中到强(高)免疫反应。COX-2表达升高与疾病特异性生存期降低(P=0.0011)、组织学分级高(P<；0.0001)、残留肿瘤大小<1 cm(P=0.0111)、年龄<57岁(P=0.0099)相关。P53或Smad4免疫染色模式改变的肿瘤与这些抑癌基因正常表达模式的肿瘤相比，COX-2的表达水平更高(分别为P<；0.0001和P=0.0004)。此外，COX-2的高表达与HER-2/neu癌基因的扩增有关(P=0.0479)。结论：COX-2的高表达与浆液性卵巢癌患者的生存率降低有关，COX-2的表达可能是通过P53、SMAD4等抑癌基因的缺失和HER-2/neu癌基因的扩增而诱导的。
Purpose and Experimental Design: Cyclooxygenase-2 (COX-2) is frequently expressed in human adenocarcinomas and inhibition of COX-2 suppresses tumor formation in various animal models of carcinogenesis. We analyzed expression of COX-2 protein in human serous ovarian carcinomas by immunohistochemistry (n = 442) and by Western blotting (n = 12) and COX-2 mRNA by reverse transcriptase PCR (n = 12). COX-2 immunoreactivity was correlated to clinicopathological variables and to expression of p53 and SMAD4 as detected by immunohistochemistry and to amplification of HER-2/neu as detected by in situ hybridization.Results: COX-2 mRNA expression was detected in 75% (9 of 12) and COX-2 protein in 42% (5 of 12) of the serous ovarian adenocarcinoma specimens as detected by reverse transcriptase-PCR and Western blot analysis, respectively. Moderate to strong (elevated) immunoreactivity for COX-2 was detected in 70% (310 of 442) of the tumors. Elevated COX-2 expression associated with reduced disease-specific survival (P = 0.0011), high histological grade (P < 0.0001), residual tumor size > 1 cm (P = 0.0111), and age > 57 years (P = 0.0099). Tumors with altered immunostaining pattern for p53 or SMAD4 expressed more frequently elevated levels of COX-2 when compared with the tumors with normal staining pattern of these tumor suppressor genes (P < 0.0001 and P = 0.0004, respectively). In addition, elevated COX-2 expression associated with amplification of HER-2/ neu oncogene (P = 0.0479).Conclusions: Our results suggest that elevated expression of COX-2 associates with reduced survival in serous ovarian carcinomas and that expression of COX-2 may be induced in these tumors by loss of tumor suppressor genes such as p53 and SMAD4 and by amplification of HER-2/neu oncogene.