COX-2: A Target for the Prevention of Cervical Cancer

COX-2：预防宫颈癌的靶点

• 批准号: 6997731
• 负责人: ANDREW Jess DANNENBERG
• 金额: $ 23.69万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-22 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6997731
• 关键词: cancer prevention; cervix neoplasms; chemoprevention; disease /disorder model; gene induction /repression; human papillomavirus; human tissue; laboratory mouse; neoplasm /cancer pharmacology; nonsteroidal antiinflammatory agent; oncoproteins; oxidoreductase inhibitor; prostaglandin E; prostaglandin endoperoxide synthase; tissue /cell culture; virus protein

Cervical cancer is the second leading cause of cancer deaths in women worldwide. Infection with high risk types of human papiliomavirus (HPV) such as HPV16 has been causally linked to cervical cancer. New medications are needed to both prevent and treat this disease. The overall goal of this application is to determine whether cyclooxygenase-2 (COX-2) represents a bona fide therapeutic target for preventing or treating cervical cancer. Several lines of evidence suggest that COX-2 is important in carcinogenesis. COX-2 deficiency protects against intestinal and skin tumor formation in animals. Moreover, selective COX-2 inhibitors suppress the formation, growth and metastasis of experimental tumors. We have discovered that levels of COX-2 are elevated in human cervical intraepithelial neoplasia and cancers. This raises the possibility that selective COX-2 inhibitors will be useful for preventing or treating cervical cancer. One aim of this proposal, therefore, is to determine whether pharmacological inhibition or genetic ablation of COX-2 inhibits cervical carcinogenesis in an animal model of cervical cancer. Additionally, we will determine whether a selective COX-2 inhibitor suppresses the growth of experimental cervical cancer and attempt to elucidate the underlying mechanism. The second aim will be to elucidate the mechanisms that account for increased expression of COX-2 and microsomal prostaglandin E synthase (mPGES) in cervical cancer. Emphasis will be placed on defining the mechanisms by which HPV16 E6 and E7 regulate the expression of both COX-2 and mPGES. Both human cell lines and tissues will be used to carry out the experiments proposed in aim two. The third aim will be to decipher the mechanism by which prostaglandin E2 induces the expression of E6 and E7 in vitro. Additionally, we will determine whether celecoxib, a selective COX-2 inhibitor, reduces E6 and E7 expression by a COX-2 independent mechanism in addition to inhibiting PGE2 biosynthesis. Finally, we will attempt to translate these in vitro findings by investigating whether celecoxib down-regulates levels of HPV16 E6 and E7 in an in vivo model of human cervical cancer. The development of a safe and effective therapy to reduce E6/E7 levels could have significant public health implications. Taken together, the results of these studies should strengthen the rationale for evaluating the utility of selective COX-2 inhibitors in the prevention and treatment of cervical cancer.

宫颈癌是全世界女性癌症死亡的第二大主要原因。具有高风险类型的人乳头状病毒（HPV）（例如HPV16）的感染与宫颈癌有因果关系。需要新的药物来预防和治疗这种疾病。该应用的总体目标是确定环氧合酶2（COX-2）是否代表了预防或治疗宫颈癌的真正治疗靶标。几条证据表明，COX-2在癌变中很重要。 COX-2缺乏可防止动物中的肠道和皮肤肿瘤形成。此外，选择性COX-2抑制剂抑制了实验肿瘤的形成，生长和转移。我们发现，在人宫内肿瘤和癌症中，COX-2的水平升高。这提高了 选择性COX-2抑制剂有可能有助于预防或治疗宫颈癌。因此，该提案的目的之一是确定COX-2的药理抑制或遗传消融是否会抑制宫颈癌动物模型中的宫颈癌。此外，我们将确定选择性COX-2抑制剂是否抑制了实验性宫颈癌的生长并试图阐明潜在机制。第二个目的是阐明宫颈癌中COX-2和微粒体前列腺素E合酶（MPGES）表达增加的机制。将重点放在定义HPV16 E6和E7调节COX-2和MPGE的表达的机制上。人类细胞系和组织都将用于进行目标二中提出的实验。第三个目的是破译前列腺素E2的机制 在体外表达E6和E7。此外，我们还将确定除了抑制PGE2生物合成之外，选择性COX-2抑制剂（一种选择性COX-2抑制剂）是否通过COX-2独立机制降低E6和E7的表达。最后，我们将尝试通过研究塞来昔布在人体宫颈癌的体内模型中调节HPV16 E6和E7的水平来转化这些体外发现。开发一种安全有效的疗法来降低E6/E7水平可能具有重大的公共卫生影响。综上所述，这些研究的结果应加强评估选择性COX-2抑制剂在预防和治疗宫颈癌的效用的基本原理。