Modulation of skin cancer by PPARBeta/delta

描述(由申请人提供)：PPARB/d(PPARB/d)基因缺失的小鼠表现出皮肤和结肠肿瘤形成增强，PPARB/d的配体激活抑制皮肤和结肠肿瘤的多样性。PPARB/d配体抑制肿瘤致瘤性的机制可能是由于诱导末端分化和增加需要PPARB/d的凋亡，因为这些效应在类似处理的PPARB/d缺失小鼠中没有发现。此外，依赖于PPARB/d对泛素介导的关键细胞增殖/凋亡途径的调节也可能是PPARB/d配体抑制肿瘤发生的核心机制。这一建议的中心假设是，PPARB/d从遗传和化学因素调节导致皮肤癌发生的分子事件。环氧合酶(COX)抑制剂抑制皮肤癌是已知的一种抑制皮肤致瘤性的方法，但不是100%有效。我们最近证明了COX抑制对化学诱导的皮肤癌的抑制不依赖于PPARB/d。另外，最近的研究表明，通过激活PPARB/d的配体来抑制细胞的增殖与抑制COX结合可以大大增强。第一个具体目的是验证这样一个假设，即结合激活PPARB/d的配体和抑制COX活性将比单独使用任何一种治疗方法都更有效地抑制皮肤癌的发生。这将通过在野生型和PPARB缺失的小鼠中进行两阶段化学致癌物测试来检验，无论是否存在COX抑制剂和/或特定的PPARB/d配体。这一联合方法的抑制作用将在肿瘤发生和发展过程中以及在已有肿瘤的小鼠身上进行检测。第二个特定目标将检验依赖PPAR？/D上调泛素C表达将减弱皮肤癌发生的假设。对角质形成细胞特异性泛素C转基因的分析将确定依赖PPARB/d调节泛素表达是否可以改善在没有依赖PPARB/d泛素C表达的情况下观察到的增强的致瘤性，并确定导致皮肤癌的关键的PPARB/d介导的泛素依赖途径。总之，这些研究将确定PPARB/d的配体激活和COX抑制是否在抑制肿瘤生长和/或肿瘤多样性方面比单一治疗更有效，并阐明PPARB/d介导的抑制化学诱导的皮肤癌变的机制。这些研究的结果将为化学预防或化疗提供有用的新靶点，这可能会导致在人类身上进行转译研究。外行相关性：在美国，每年有100多万例皮肤癌被诊断出来。所有癌症每年的成本超过数十亿美元。皮肤癌的风险因素包括紫外线和暴露在环境化学致癌物中。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，确定皮肤癌发生的关键阶段，其中PPARB依赖调控是显著的，并提供新的分子靶点，以抑制/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.