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

宫颈癌是全球女性癌症死亡的第二大原因。感染高危类型的人乳头瘤病毒(HPV)，如HPV16，已被认为与宫颈癌有关。需要新的药物来预防和治疗这种疾病。这项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点。一些证据表明，COX-2在癌症的发生过程中起着重要作用。COX-2缺乏对动物肠道和皮肤肿瘤的形成具有保护作用。此外，选择性COX-2抑制剂可抑制实验性肿瘤的形成、生长和转移。我们发现COX-2在宫颈上皮内瘤变和癌组织中的表达水平升高。这引发了 选择性COX-2抑制剂用于预防或治疗宫颈癌的可能性。因此，这项建议的目的之一是确定药物抑制或基因切除COX-2是否能抑制宫颈癌动物模型的宫颈癌发生。此外，我们将确定选择性COX-2抑制剂是否抑制实验性宫颈癌的生长，并试图阐明其潜在机制。第二个目的是阐明宫颈癌中COX-2和微粒体前列腺素E合成酶(MPGES)表达增加的机制。重点是确定HPV16E6和E7调节COX-2和mPGES表达的机制。人体细胞系和组织都将被用来进行目标二中提出的实验。第三个目标将是破译前列腺素E_2诱导 E6和E7在体外的表达。此外，我们将确定选择性COX-2抑制剂塞来昔布除了抑制PGE2的生物合成外，是否还通过COX-2非依赖机制减少E6和E7的表达。最后，我们将试图通过研究塞来昔布是否下调人宫颈癌体内模型中HPV16E6和E7的水平来翻译这些体外研究结果。开发一种安全有效的治疗方法来降低E6/E7水平可能会对公共卫生产生重大影响。综上所述，这些研究的结果应该会加强评价选择性COX-2抑制剂在预防和治疗宫颈癌中的有效性的理论基础。

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.