Kulkarni S, Rader J S, Zhang F, Liapis H, Koki A T, Masferrer J L, Subbaramaiah K, Dannenberg A J
Department of Medicine, New York Presbyterian Hospital-Cornell, New York 10021, USA.
Clin Cancer Res. 2001 Feb;7(2):429-34.
Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) is an important target for preventing epithelial malignancies. Little is known, however, about the expression of COX-2 in gynecological malignancies. By immunoblot analysis, COX-2 was detected in 12 of 13 cases of cervical cancer but was undetectable in normal cervical tissue. Immunohistochemistry revealed COX-2 in malignant epithelial cells. COX-2 was also expressed in cervical intraepithelial neoplasia. The mechanism by which COX-2 is up-regulated in cervical cancer is unknown. Because the epidermal growth factor (EGF) receptor is commonly overexpressed in cervical cancer, we investigated whether EGF could induce COX-2 in cultured human cervical carcinoma cells. Treatment with EGF markedly induced COX-2 protein, COX-2 mRNA, and stimulated COX-2 promoter activity. The induction of COX-2 by EGF was suppressed by inhibitors of tyrosine kinase activity, phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p38 mitogen-activated protein kinase. Moreover, overexpressing dominant-negative forms of extracellular signal-regulated kinase 1, c-Jun NH2-terminal kinase, p38, and c-Jun blocked EGF-mediated induction of COX-2 promoter activity. Taken together, these findings suggest that deregulation of the EGF receptor signaling pathway may lead to enhanced COX-2 expression in cervical cancer.
多项证据表明，环氧化酶-2（COX-2）是预防上皮性恶性肿瘤的重要靶点。然而，关于COX-2在妇科恶性肿瘤中的表达情况却知之甚少。通过免疫印迹分析，在13例宫颈癌病例中有12例检测到COX-2，但在正常宫颈组织中未检测到。免疫组织化学显示恶性上皮细胞中有COX-2。COX-2在宫颈上皮内瘤变中也有表达。COX-2在宫颈癌中上调的机制尚不清楚。由于表皮生长因子（EGF）受体在宫颈癌中通常过度表达，我们研究了EGF是否能在培养的人宫颈癌细胞中诱导COX-2。用EGF处理显著诱导了COX-2蛋白、COX-2 mRNA，并刺激了COX-2启动子活性。酪氨酸激酶活性抑制剂、磷脂酰肌醇3激酶、丝裂原活化蛋白激酶激酶和p38丝裂原活化蛋白激酶可抑制EGF对COX-2的诱导。此外，过表达细胞外信号调节激酶1、c-Jun氨基末端激酶、p38和c-Jun的显性负性形式可阻断EGF介导的COX-2启动子活性诱导。综上所述，这些发现表明EGF受体信号通路失调可能导致宫颈癌中COX-2表达增强。
