Modulation of skin cancer by PPARBeta/delta

描述（由申请人提供）：过氧化物酶体增殖物激活受体b /d （PPARB/d）无效小鼠在皮肤和结肠中均表现出增强的肿瘤形成，并且PPARB/d的配体激活抑制皮肤和结肠中的肿瘤多样性。PPARB/d配体抑制致瘤性的机制可能是由于诱导终末分化和增加细胞凋亡，这需要PPARB/d，因为这些作用在类似处理的PPARB/d缺失小鼠中没有发现。此外，PPARB/d依赖于泛素介导的关键细胞增殖/凋亡通路的调节也可能是PPARB/d配体抑制致瘤性的核心机制。该建议的中心假设是PPARB/d从遗传和化学因素调节导致皮肤癌的分子事件。环氧化酶（COX）抑制剂抑制皮肤癌变是已知的一种抑制皮肤致瘤性的方法，但并非100%有效。我们最近证明，COX抑制对化学诱导的皮肤癌的抑制与PPARB/d无关。此外，最近其他研究表明，PPARB/d配体激活对细胞增殖的抑制作用在与COX的抑制作用结合时可以大大增强。第一个具体目的是验证PPARB/d配体激活与COX活性抑制相结合的假设，其抑制皮肤癌变的效果优于单独治疗。在存在或不存在COX抑制剂和/或特定的PPARB/d配体的情况下，将在野生型和PPARB缺失小鼠中通过两阶段化学致癌物质测试来检验这一点。这种联合方法的抑制作用将在肿瘤发生和发展期间以及已有肿瘤的小鼠中进行检查。第二个具体目标将检验PPAR？/d依赖性的泛素C表达上调将减轻皮肤癌的发生。角化细胞特异性泛素C转基因分析将确定PPARB/d依赖性泛素C表达的调节是否可以改善在缺乏PPARB/d依赖性泛素C表达时观察到的增强的致瘤性，并确定导致皮肤癌的关键PPARB/d介导的泛素依赖性途径。总的来说，这些研究将确定PPARB/d配体激活与COX抑制相结合是否比单独治疗更有效地抑制肿瘤生长和/或肿瘤多样性，并阐明PPARB/d介导的化学诱导的皮肤癌变的抑制机制。这些研究的结果将为化学预防或化疗提供有用的新靶点，这可能会导致人类的转化研究。相关性：在美国，每年有超过100万例皮肤癌被诊断出来。所有癌症每年的费用超过数十亿美元。皮肤癌的危险因素包括紫外线和接触环境中的化学致癌物。这些研究的结果将确定联合方法是否可以更有效地抑制皮肤癌，确定pparb依赖性调节显著的皮肤癌发生的关键阶段，并为抑制/预防化学诱导的皮肤癌提供新的分子靶点。

DESCRIPTION (provided by applicant): Peroxisome proliferator-activated receptor-B/d (PPARB/d)-null mice exhibit enhanced tumor formation in both skin and colon and ligand activation of PPARB/d inhibits tumor multiplicity in both skin and colon. The mechanisms underlying the inhibition of tumorigenicity by a PPARB/d ligand is likely due to the induction of terminal differentiation and increased apoptosis that requires PPARB/d since these effects are not found in similarly treated PPARB/d-null mice. Additionally, PPARB/d-dependent modulation of ubiquitin-mediated regulation of critical cell proliferation/apoptotic pathways could also be a central mechanism underlying the inhibition of tumorigenicity by PPARB/d ligands. The central hypothesis of this proposal is that the PPARB/d modulates the molecular events that lead to skin carcinogenesis from genetic and chemical factors. Inhibition of skin carcinogenesis by cyclooxygenase (COX) inhibitors is 1 approach that is known to inhibit skin tumorigenicity, but is not 100% effective. We have recently demonstrated that inhibition of chemically-induced skin cancer by COX inhibition is independent of PPARB/d. Additionally, others have recently shown that inhibition of cell proliferation by ligand activation of PPARB/d can be greatly enhanced when coupled with inhibition of COX. The first specific aim is to test the hypothesis that combining ligand activation of PPARB/d with inhibition of COX activity will inhibit skin carcinogenesis with greater efficacy than either treatment by itself. This will be examined by 2-stage chemical carcinogen testing in wild-type and PPARB-null mice, in the presence or absence of COX inhibitors and/or a specific PPARB/d ligand. The inhibitory action of this combined approach will be examined during tumor initiation and progression, and in mice with pre-existing tumors. The second specific aim will test the hypothesis that PPAR?/d-dependent up-regulation of ubiquitin C expression will attenuate skin carcinogenesis. Analysis of keratinocyte-specific ubiquitin C transgenic will determine if PPARB/d-dependent modulation of ubiquitin expression can ameliorate the enhanced tumorigenicity observed in the absence of PPARB/d-dependent ubiquitin C expression, and identify critical PPARB/d-mediated, ubiquitin-dependent pathways that lead to skin cancer. Collectively, these studies will determine if combining ligand activation of PPARB/d with COX inhibition has greater efficacy at inhibiting tumor growth and/or tumor multiplicity than either single treatment and elucidate the mechanisms of PPARB/d-mediated inhibition of chemically-induced skin carcinogenesis. Results from these studies will provide useful novel targets for chemoprevention or chemotherapy that will likely lead to translational research in humans. Lay relevance: More than 1 million cases of skin cancer are diagnosed annually within the United States. The annual cost of all cancers exceeds billions of dollars. Risk factors for skin cancer include UV light and exposure to environmental chemical carcinogens. Results from these studies will determine if a combinational approach can more effectively inhibit skin cancer, determine the critical stage of skin carcinogenesis where PPARB-dependent regulation is significant, and provide new molecular targets to inhibit/prevent chemically-induced skin cancer.