DISSECTING COX-1 RELATED GENE PATHWAYS IN OVARIAN CANCER

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 剖析卵巢癌中 COX-1 相关基因通路 摘要 卵巢癌是美国妇科癌症死亡的主要原因。 由环氧合酶 1 (COX-1) 和环氧合酶 2 (COX-2) 介导的前列腺素 (PG) 途径与排卵有关，并被认为是卵巢癌病因学中的潜在因素。 初步数据：我们利用 cDNA 微阵列将正常卵巢组织样本与卵巢癌进行比较，通过这一过程，我们发现癌症中 COX-1 的表达水平高出 2 倍以上。 我们的合作者发表的数据同样表明，COX-1 而不是 COX-2 在卵巢恶性肿瘤中高表达。 假设和目的：本研究的长期目标是确定 COX-1 对卵巢癌发生的具体贡献。 我们假设在卵巢癌中，COX-1 诱导 PGE2 产生，其目标是磷脂酰肌醇 3 激酶/蛋白激酶 B (PI3K/AKT) 信号传导以及该通路中参与肿瘤生长和进展的成分。 我们建议使用定制的组织芯片进行免疫组织化学 (IHC) 染色来测量 COX-1、COX-2 和与 PI3K 相关的分子标记物的表达水平：磷酸化 AKT (pAKT)、缺氧诱导因子 (HIF-1a) 和血管内皮生长因子 (VEGF)。 将进行平行体外实验，通过用选择性 COX-1 抑制剂 SC-560 处理表达 COX-1 的细胞系 OVCAR3 来进一步评估 COX-1 功能。 我们将测量 PGE2 代谢、细胞生长、凋亡、迁移和侵袭，以及 PI3K、pAKT、HIF-1a 和 VEGF 的表达水平。 我们还将利用 cDNA 微阵列生成与 COX-1 相关的基因谱。 意义：如果我们确定 COX-1 确实是卵巢癌肿瘤进展的一个重要因素，这项研究可能为其未来用作治疗这种致命疾病的生物标志物和治疗靶点奠定基础。 具体目的：环加氧酶 1（COX-1 和环加酶 2 (COX-2)）介导的前列腺素 (PG) 途径与排卵有关，并被认为是卵巢癌病因学的潜在因素。本研究的长期目标是确定 COX-1 对卵巢癌发生的具体贡献。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dissecting COX-1 Related Gene Pathways in Ovarian Cancer ABSTRACT Ovarian cancer is the leading cause of death among gynecologic cancers in the United States. The prostaglandin (PG) pathway mediated by cyclooxygenase-1 (COX-1) and the cycloogygenase-2 (COX-2) enzymes is implicated in ovulation and has been suggested as a potential factor in the etiology of ovarian cancer. Preliminary Data: We have utilized cDNA microarrays to compare normal ovarian tissue samples to ovarian carcinomas, and through this process have shown expression levels of COX-1 to be more than 2-fold higher in the cancers. Data published by our collaborators similarly demonstrates that COX-1, not COX-2, is highly expressed in ovarian malignancies. Hypothesis and Aims: The long-range goal of this research is to determine the specific contributions of COX-1 to ovarian carcinogenesis. We hypothesize that in ovarian cancers, COX-1 induces PGE2 production, which targets phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling and components of this pathway that are involved in tumor growth and progression. We propose the use of custom-made tissue arrays for immunohistochemistry (IHC) staining to measure expression levels of COX-1, COX-2 and molecular markers associated with PI3K: phosphorylated AKT (pAKT), hypoxia induced factor (HIF-1a) and vascular endothelial growth factor (VEGF). Parallel in vitro experiments will be performed to further evaluate COX-1 function by treating a COX-1 expressing cell line, OVCAR3, with a selective COX-1 inhibitor, SC-560. We will measure PGE2 metabolism, cell growth, apoptosis, migration and invasion, as well as expression levels of PI3K, pAKT, HIF-1a and VEGF. We will also utilize cDNA microarrays to generate gene profiles that are associated with COX-1. Significance: If we determine that COX-1 is indeed a prominent factor in tumor progression in ovarian cancer, this research may provide the basis for its future use as a biomarker and target for therapy in the management of this deadly disease. Specific Aims: The prostaglandin (PG) pathway mediated by cyclooxygenase-1 (COX-1 and cycloogygenase-2 (COX-2) enzymes is implicated in ovulation and has been suggested as a potential factor in the etiology of ovarian cancer. The long-range goal of this research is to determine the specific contributions of COX-1 to ovarian carcinogenesis.