Role of PPARbeta in colon carcinogenesis

描述(申请人提供)：自1994年首次被鉴定为过氧化物酶体增殖物激活受体(PPAR)的成员以来，PPAR-β(也被称为PPAR-Delta)的具体作用仍然不清楚，最近的数据表明PPAR-β可能参与包括皮肤和结肠在内的上皮性癌症。PPAR-β在局部应用肿瘤促进剂(TPA)后上调，在具有失活APC基因的人结肠肿瘤细胞中，以及在人和偶氮甲烷诱导的啮齿动物结肠肿瘤中，首次提供了证据表明该受体参与了上皮性癌症的机制。突变的APC基因导致β-连环蛋白表达增加，介导了结肠癌细胞中PPAR-β的转录上调，表明PPAR-β的激活位于结肠癌病因学初始分子事件的下游。这一建议的中心假设是PPAR-β的一个功能作用是调节导致结肠癌发生的靶基因表达。第一个具体目标是开发两个模型系统来检验PPAR-β在结肠癌发生中必不可少的假设。第一个模型将利用PPAR-β缺失小鼠与APC MIN+/-小鼠的杂交，第二个模型将评估偶氮甲烷诱导的PPAR-β缺失小鼠的结肠癌。这些实验的结果将确定PPAR-β表达增加是否是结肠癌发病机制的核心。在人类和动物模型中，高脂肪含量的西式饮食与结肠癌的高发病率有关，饮食中的脂肪酸是已知的PPAR-β的配体。第二个具体目标将检验这样的假设，即高脂肪饮食导致的结肠癌增加依赖于PPAR-β。非类固醇抗炎药(NSAIDs)用于预防结肠癌的形成，可能是由于抑制PPAR-β依赖的靶基因转录和/或抑制COX代谢。初步数据表明，舒林酸的有益作用是由PPAR-β介导的。第三个特定目的将确定非甾体抗炎药舒林酸对结肠癌的抑制是否由PPAR-β介导。这项工作的结果还将确定抑制PPAR-β依赖的靶基因转录，抑制可能受PPAR-β影响的COX活性，或两者兼而有之，是舒林酸抑制结肠癌的关键机制。结合这项工作，这项工作将阐明PPAR-β在遗传、饮食和化学诱导的结肠癌潜在的分子机制以及在预防这种疾病中的特定功能作用；从而提供未来预防结肠癌的治疗目标。

DESCRIPTION (provided by applicant): Since it was first identified as a member of the peroxisome proliferator-activated receptors (PPARs) in 1994, specific roles for the PPAR-beta (also referred to as PPAR-delta) have remained elusive, Recent data suggests that the PPAR-beta may be involved in epithelial cancer including skin and colon. PPAR-beta expression is upregulated in response to topical application of a tumor promoter (TPA), in human colon tumor cells with an inactivated APC gene, and in human and azoxymethane-induced rodent colon tumors providing the first evidence suggesting that this receptor contributes to the mechanisms of epithelial cancers. Increased expression of beta-catenin caused by a mutant APC gene mediates transcriptional upregulation of PPAR-beta in colon tumor cells, demonstrating that PPAR-beta activation is downstream of the initial molecular events in the etiology of colon cancer. The central hypothesis of this proposal is that one functional role for PPAR-beta is to modulate target gene expression that leads to colon carcinogenesis. The first specific aim is to develop two model systems to test the hypotheses that PPAR-beta is essential for colon carcinogenesis. The first model will utilize crossing the PPAR-beta-null mouse line with APC min+/- mice and the second model will assess azoxymethane-induced colon cancer in the PPAR-beta null mouse. Results from these experiments will determine if increased PPAR-beta expression is central to the mechanisms underlying colon cancer. Western-style diets with a high fat content have been linked to higher incidence of colon cancer in both human and animal models and dietary fatty acids are known ligands for PPAR-beta. The second specific aim will test the hypothesis that increased colon cancer resulting from a high fat diet is dependent on PPAR-beta. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is used to prevent colon tumor formation, and may be due to inhibition of PPAR-beta-dependent target gene transcription and/or inhibition of COX metabolism. Preliminary data suggests that the beneficial effects of sulindac are mediated by the PPAR-beta. The third specific aim will determine if inhibition of colon carcinogenesis by the NSAID sulindac is mediated by PPAR-beta. Results from this work will also determine whether inhibition of PPAR-beta-dependent target gene transcription, inhibition of COX activity that may be influenced by PPAR-beta, or both, are critical to the mechanisms underlying sulindac inhibition of colon cancer. Combined, this work will clarify specific functional roles for the PPAR-beta in the molecular mechanisms underlying genetic, dietary and chemically induced colon cancer and in the prevention of this disease; thus providing future therapeutic targets to prevent colon cancer.