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）缺失小鼠在皮肤和结肠中均表现出增强的肿瘤形成，PPARB/d的配体激活抑制皮肤和结肠中的肿瘤多样性。PPARB/d配体抑制致瘤性的潜在机制可能是由于需要PPARB/d诱导终末分化和增加细胞凋亡，因为在类似处理的PPARB/d-缺失小鼠中未发现这些作用。此外，PPARB/d依赖性的泛素介导的关键细胞增殖/凋亡途径的调节也可能是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调节遗传和化学因素导致皮肤癌发生的分子事件。通过环氧合酶（考克斯）抑制剂抑制皮肤癌发生是已知抑制皮肤致瘤性的一种方法，但不是100%有效。我们最近证实，通过抑制考克斯抑制化学诱导的皮肤癌是不依赖于PPARB/d的。 此外，其他人最近已经表明，当与考克斯的抑制结合时，通过PPARB/d的配体活化对细胞增殖的抑制可以大大增强。第一个具体目的是检验PPARB/d的配体活化与考克斯活性抑制相结合将比单独治疗更有效地抑制皮肤癌发生的假设。在存在或不存在考克斯抑制剂和/或特异性PPARB/d配体的情况下，通过野生型和PPARB缺失小鼠的2阶段化学致癌物试验对此进行检查。将在肿瘤起始和进展期间以及在具有预先存在的肿瘤的小鼠中检查这种组合方法的抑制作用。第二个具体目标将测试假设，泛素C表达的依赖性上调将减弱皮肤癌的发生。角化细胞特异性泛素C转基因的分析将确定是否PPARB/d依赖的泛素表达的调节可以改善在PPARB/d依赖的泛素C表达的情况下观察到的增强的致瘤性，并鉴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的配体活化与考克斯抑制的组合是否比任一单一治疗在抑制肿瘤生长和/或肿瘤多样性方面具有更大的功效，并阐明PPARB/d介导的化学诱导的皮肤致癌作用的抑制机制。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。在美国，每年诊断出超过100万例皮肤癌病例。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暴露于环境化学致癌物。这些研究的结果将确定组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，并提供新的分子靶点来抑制/预防化学诱导的皮肤癌。

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.