Role of the EP1 prostanoid receptor in UV carcinogenesis

描述（由申请方提供）：紫外线B（UVB）是急性和长期暴露后大多数皮肤损伤的原因，并且被认为是非黑色素瘤皮肤癌（NMSC）发展中最重要的单一病原体。这些皮肤肿瘤是迄今为止人类最常见的癌症形式，每年在美国发现超过100万例新病例。最近发现UVB致癌作用与炎症反应有关，包括环氧合酶-2（考克斯-2）基因的增加和随后前列腺素E2（PGE 2）的升高。考克斯-2诱导和随后PGE 2产生在皮肤肿瘤形成中的重要性已在考克斯-2敲除小鼠以及使用特异性考克斯-2抑制剂塞来昔布的研究中得到证实。PGE 2的生物学作用归因于其通过四种主要受体EP的信号传导[1-4]。特异性EP受体拮抗剂的最新发展使得通过阻断PGE 2与特异性EP受体的结合来评估PGE 2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重要的特定EP受体尚未被确定。拟议研究的基本假设是，通过EP 1受体的PGE 2信号传导有助于UVB暴露后发生的急性变化，以及对慢性UVB暴露的肿瘤发展作出反应。第一个特定目的的研究将检查通过单独给予特异性EP 1受体拮抗剂ONO-8713或与塞来昔布（一种特异性考克斯-2抑制剂）联合给药阻断EP 1受体活性对急性UVB介导的皮肤炎症反应的影响。具体目标2中的研究将检查通过特异性EP 1受体拮抗剂ONO-8713单独给药或与塞来昔布（一种特异性考克斯-2抑制剂）联合给药阻断EP 1受体活性对肿瘤促进、进展和消退的影响。最后，具体目标3中的研究将通过测试与Skh/hr无毛小鼠回交的EP 1 KO小鼠对UVB诱导的皮肤致癌作用的敏感性，直接证明EP 1信号传导在UVB诱导的皮肤致癌作用中的重要性。这些研究提供了一个独特的机会，以深入了解EP 1受体在皮肤癌变过程中的作用，并可能提供一个重要的药理学方法，以防止或逆转阳光照射的破坏性影响。

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.