Role of the EP1 prostanoid receptor in UV carcinogenesis

描述（由申请人提供）：紫外线B （UVB）是导致急性和长期暴露后大部分皮肤损伤的原因，被认为是非黑色素瘤皮肤癌（NMSC）发展中最重要的单一病因。这些皮肤肿瘤是迄今为止人类最常见的癌症，在美国每年有超过100万的新病例被发现。最近，人们发现UVB致癌与炎症反应有关，炎症反应包括环氧化酶-2 （COX-2）基因的增加和随后前列腺素E2 （PGE2）的升高。COX-2基因敲除小鼠以及使用特异性COX-2抑制剂塞来昔布的研究都证明了COX-2诱导和随后PGE2产生在皮肤肿瘤形成中的重要性。PGE2的生物学作用归因于其通过四种主要受体EP发出信号[1-4]。最近特异性EP受体拮抗剂的发展使得通过阻断PGE2与特异性EP受体的结合来评估PGE2对致癌过程的贡献成为可能。虽然对乳腺癌和结肠癌的研究表明，特定的EP受体刺激肿瘤的发展，但在UVB诱导的皮肤癌发生中起重要作用的特定EP受体尚未被确定。提出的研究的基本假设是，通过EP1受体的PGE2信号传导有助于中波紫外线暴露后发生的急性变化，以及慢性中波紫外线暴露后肿瘤的发展。第一个特定目标的研究将通过单独或与特异性COX-2抑制剂塞来昔布（celecoxib）联合施用特异性EP1受体拮抗剂ONO-8713，来检测阻断EP1受体活性对急性uvb介导的皮肤炎症反应的影响。特异性目的2的研究将通过单独使用特异性EP1受体拮抗剂ONO-8713或与特异性COX-2抑制剂塞来昔布（celecoxib）联合使用阻断EP1受体活性对肿瘤促进、进展和消退的影响。最后，具体目的3中的研究将通过测试与Skh/hr无毛小鼠回交的EP1 KO小鼠对uvb诱导的皮肤癌的易感性，直接证明EP1信号在uvb诱导的皮肤癌发生中的重要性。这些研究为深入了解EP1受体在皮肤癌发生过程中的作用提供了一个独特的机会，并可能为预防或逆转阳光照射的破坏性影响提供重要的药理学方法。

DESCRIPTION (provided by applicant): Ultraviolet light B (UVB) is responsible for the majority of cutaneous damage following both acute and long term exposure and is believed to be the single most important etiologic agent in non-melanoma skin cancers (NMSC) development. These skin tumors are by far the most common form of cancer in humans, with over 1 million new cases identified in the United States each year. UVB carcinogenesis has recently been associated with an inflammatory response that includes increases in the cyclooxygenase-2 (COX-2) gene and the subsequent elevation of prostaglandin E2 (PGE2). The importance of COX-2 induction and subsequent PGE2 production in skin tumor formation has been demonstrated in both COX-2 knockout mice as well as in studies using the specific COX-2 inhibitor, celecoxib. The biological actions of PGE2 have been attributed to its signaling through four main receptors EP[1-4]. The recent development of specific EP receptor antagonists now makes it possible to evaluate the contribution of PGE2 to the carcinogenic process by blocking its binding to specific EP receptor(s). While studies in both breast and colon cancer suggest that specific EP receptors stimulate tumor development, the particular EP receptors important in UVB induced skin carcinogenesis have not been identified. The underlying Hypothesis for the proposed studies is that PGE2 signaling through the EP1 receptor contributes to both the acute changes that occur following UVB exposure, as well as to tumor development in response to chronic UVB exposure. Studies in the first specific aim will examine the effects of blocking EP1 receptor activity via administration of the specific EP1 receptor antagonist ONO-8713 alone or in combination with celecoxib, a specific COX-2 inhibitor, on the acute UVB-mediated cutaneous inflammatory response. Studies in specific aim 2 will examine the effects of blocking EP1 receptor activity via administration of the specific EP1 receptor antagonist ONO-8713 alone or in combination with celecoxib, a specific COX-2 inhibitor, on tumor promotion, progression and regression. Finally studies in specific aim 3 will demonstrate directly the importance of EP1 signaling in UVB-induced skin carcinogenesis by testing the susceptibility of EP1 KO mice backcrossed to Skh/hr hairless mice to UVBinduced skin carcinogenesis. These studies offer a unique opportunity to gain insight into the role of the EP1 receptor in the skin carcinogenesis process and potentially provide an important pharmacological approach to preventing or reversing the damaging effects of sunlight exposure.