Erkinheimo Tiina-Liisa, Lassus Heini, Finne Patrik, van Rees Bastiaan P, Leminen Arto, Ylikorkala Olavi, Haglund Caj, Butzow Ralf, Ristimäki Ari
Department of Obstetrics and Gynecology, Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Clin Cancer Res. 2004 Jan 15;10(2):538-45. doi: 10.1158/1078-0432.ccr-0132-03.
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.
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).
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/neuoncogene.
环氧化酶-2（COX-2）在人类腺癌中常呈高表达，在多种致癌动物模型中，抑制COX-2可抑制肿瘤形成。我们通过免疫组织化学法（n = 442）和蛋白质印迹法（n = 12）分析了人浆液性卵巢癌中COX-2蛋白的表达情况，并通过逆转录聚合酶链反应（n = 12）分析了COX-2 mRNA的表达情况。通过免疫组织化学检测COX-2免疫反应性与临床病理变量、p53和SMAD4的表达相关，通过原位杂交检测COX-2免疫反应性与HER-2/neu扩增相关。
通过逆转录聚合酶链反应和蛋白质印迹分析，分别在75%（12例中的9例）的浆液性卵巢腺癌标本中检测到COX-2 mRNA表达，在42%（12例中的5例）的标本中检测到COX-2蛋白表达。在70%（442例中的310例）的肿瘤中检测到COX-2呈中度至强（升高）免疫反应性。COX-2表达升高与疾病特异性生存率降低（P = 0.0011）、高组织学分级（P < 0.0001）、残留肿瘤大小>1 cm（P = 0.0111）以及年龄>57岁（P = 0.0099）相关。与这些肿瘤抑制基因染色模式正常的肿瘤相比，p53或SMAD4免疫染色模式改变的肿瘤中COX-2表达水平升高更为常见（分别为P < 0.0001和P = 0.0004）。此外，COX-2表达升高与HER-2/neu癌基因扩增相关（P = 0.0479）。
我们的结果表明，COX-2表达升高与浆液性卵巢癌生存率降低相关，并且在这些肿瘤中，COX-2的表达可能由肿瘤抑制基因如p53和SMAD4的缺失以及HER-2/neu癌基因的扩增所诱导。
