DISSECTING COX-1 RELATED GENE PATHWAYS IN OVARIAN CANCER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。卵巢癌是美国妇科癌症死亡的主要原因。由环氧化酶-1 （COX-1）和环氧化酶-2 （COX-2）酶介导的前列腺素（PG）通路与排卵有关，已被认为是卵巢癌病因的一个潜在因素。初步数据：我们利用cDNA微阵列技术将正常卵巢组织样本与卵巢癌组织样本进行比较，结果显示COX-1在肿瘤组织中的表达水平高出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。假设与目的：本研究的长期目标是确定COX-1在卵巢癌发生中的具体作用。我们假设在卵巢癌中，COX-1诱导PGE2的产生，PGE2靶向磷脂酰肌醇3激酶/蛋白激酶B （PI3K/AKT）信号通路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阵列进行免疫组化（IHC）染色来测量COX-1， COX-2和PI3K相关的分子标记的表达水平：磷酸化AKT (pAKT)，缺氧诱导因子（HIF-1）和血管内皮生长因子（VEGF）。通过使用选择性COX-1抑制剂SC-560处理表达COX-1的细胞系OVCAR3，将进行平行的体外实验，进一步评估COX-1的功能。我们将测量PGE2代谢、细胞生长、凋亡、迁移和侵袭，以及PI3K、pAKT、HIF-1？和VEGF。我们还将利用cDNA微阵列来生成与COX-1相关的基因图谱。意义：如果我们确定COX-1确实是卵巢癌肿瘤进展的重要因素，本研究可能为其未来作为这种致命疾病管理的生物标志物和治疗靶点提供基础。

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. 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 cyclooxygenase-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-1?) 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-1? 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.