Yang Wan-Lin, Roland Isabelle H, Godwin Andrew K, Xu Xiang-Xi
Ovarian Cancer and Tumor Cell Biology Programs, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Oncogene. 2005 Dec 1;24(54):7991-8002. doi: 10.1038/sj.onc.1208943.
Cyclooxygenase 2 (COX-2) is often found overexpressed in cancer and is thought to have a role in carcinogenic promotion, and thus is a target for therapeutic intervention. Here, we investigated the regulation of COX-2 expression in normal and cancer ovarian surface epithelial cells. Tumor necrosis factor alpha (TNF-alpha) is a potent inducer of COX-2 expression in the ovarian surface epithelium and this regulation is a critical step in ovulation. We observed that TNF-alpha stimulated COX-2 expression in human primary and immortalized epithelial (HIO) cell lines. The stimulation was suppressed by inhibitors of several signaling pathways, indicating the collaboration of TNF-alpha-activated signaling pathways mediates the regulation of COX-2 expression. In five ovarian cancer cell lines analysed, four did not express detectable COX-2 and TNF-alpha failed to elicit COX-2 expression. In NIH:OVCAR-5, the only ovarian cancer cell line expressing COX-2, signal pathway inhibitors no longer affected TNF-alpha-induced COX-2 expression. Thus, we conclude that TNF-alpha mediated signaling is uncoupled from the modulation of COX-2 expression in ovarian cancer. The loss of COX-2 expression was also observed to associate closely with epithelial neoplastic morphological transformation. The frequent loss of COX-2 expression suggests in ovarian cancer, unlike in other epithelial cancers, COX-2 expression does not contribute to ovarian cancer malignancy.
环氧化酶2（COX - 2）在癌症中常被发现过度表达，并且被认为在致癌促进过程中发挥作用，因此是治疗干预的一个靶点。在此，我们研究了正常和癌性卵巢表面上皮细胞中COX - 2表达的调控。肿瘤坏死因子α（TNF -α）是卵巢表面上皮中COX - 2表达的强效诱导剂，这种调控是排卵的关键步骤。我们观察到TNF -α刺激人原代和永生化上皮（HIO）细胞系中COX - 2的表达。这种刺激被几种信号通路的抑制剂所抑制，表明TNF -α激活的信号通路协同介导了COX - 2表达的调控。在分析的五种卵巢癌细胞系中，四种未检测到COX - 2表达，TNF -α也未能引发COX - 2表达。在NIH:OVCAR - 5（唯一表达COX - 2的卵巢癌细胞系）中，信号通路抑制剂不再影响TNF -α诱导的COX - 2表达。因此，我们得出结论，在卵巢癌中，TNF -α介导的信号传导与COX - 2表达的调节解偶联。还观察到COX - 2表达的缺失与上皮肿瘤形态学转变密切相关。COX - 2表达的频繁缺失表明，与其他上皮癌不同，在卵巢癌中COX - 2表达对卵巢癌的恶性程度没有影响。
