Modulation of liver cancer by PPARbeta/delta

描述（由申请人提供）：每年有超过14，000人死于肝癌，这是美国增长最快的癌症类型。与其他癌症相比，肝癌的发病率和死亡率正在增加。由于目前的化疗和手术治疗策略不是很有效，因此明显需要新的方法来预防和治疗这种疾病。因此，有必要描绘参与肝癌病因学的新分子途径，以提供具有显著更好疗效的新策略来预防肝癌所致的人类死亡。已经证实，过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptor，PPAR 1）对靶基因的直接转录上调可以调节细胞内稳态。然而，也有证据表明，PPAR/具有表观遗传活性，包括通过与其他转录因子相互作用抑制促炎细胞因子、趋化因子和细胞粘附分子的表达。初步数据表明，PPAR/可以减轻肝毒性和癌前肝肿瘤形成。此外，PPARi的配体活化可以通过下调促炎信号传导分子来减弱肝毒性。该提议的中心假设是，PPAR/可以特异性地靶向抑制肝癌发生。目的1将检验在肝癌发生过程中PPAR/减弱肿瘤促进的假设。这将通过使用化学诱导的模型或HCV转基因模型使用野生型和Ppar/-缺失小鼠诱导肝癌，结合用高亲和力PPAR/配体GW 0742治疗来检查。目的2将检验这样的假设，即PPAR/通过Kupffer细胞中炎症信号的表观遗传调节来减弱肿瘤促进。这将通过分析表达DNA结合结构域突变形式的PPARl的转基因小鼠来检查，所述PPARl可以与其他转录因子表观遗传学相互作用，但不能激活PPRE特异性靶基因。该分析还将与枯否细胞中的PPAR/的条件性缺失的分析结合。这些创新研究的结果将确定PPAR/是否可以成为抗炎分子靶点，并为预防和治疗肝癌提供替代策略。此外，如果证明PPAR介导的炎症信号传导的表观遗传调节可有效预防肝癌发生，这些研究的结果可能会导致肝癌和其他慢性炎症性疾病治疗策略的重大范式转变。

DESCRIPTION (provided by applicant): There are more than 14,000 deaths per year due to liver cancer, the most rapidly increasing type of cancer in the United States. In contrast to other cancers, liver cancer frequency and mortality is increasing. There is a distinct need for new approaches to prevent and treat this disease as the current strategies of chemotherapy and surgical treatments are not very effective. Thus, it is essential to delineate new molecular pathways involved in the etiology of liver cancer to provide new strategies with significantly better efficacy to prevent human mortality due to liver cancer. It well established that direct transcriptional up-regulation of target genes by peroxisome proliferator-activated receptor-/ (PPAR/) can modulate cellular homeostasis. However, there is also evidence that PPAR/ has epigenetic activities that include inhibiting expression of proinflammatory cytokines, chemokines and cell adhesion molecules via interacting with other transcription factors. Preliminary data demonstrates that PPAR/ can attenuate liver toxicity and pre-malignant liver tumor formation. Further, ligand activation of PPAR/ can attenuate liver toxicity by down-regulating pro- inflammatory signaling molecules. The central hypothesis of this proposal is that PPAR/ can be specifically targeted to inhibit hepatocarcinogenesis. Aim 1 will test the hypothesis that PPAR/ attenuates tumor promotion during hepatocarcinogenesis. This will be examined by inducing liver cancer using either a chemically-induced model or an HCV-transgenic model using both wild-type and Ppar/-null mice, coupled with treatment with the high affinity PPAR/ ligand GW0742. Aim 2 will test the hypothesis that PPAR/ attenuates tumor promotion by epigenetic modulation of inflammatory signaling in Kupffer cells. This will be examined by analysis of transgenic mice expressing a DNA binding domain mutant form of PPAR/ that can epigenetically interact with other transcription factors, but is incapable of activating PPRE-specific target genes. This analysis will also be coupled with analysis of conditional deletion of PPAR/ in Kupffer cells. Results from these innovative studies will determine if PPAR/ can be an anti-inflammatory molecular target and provide an alternative strategy for preventing and treating liver cancer. Additionally, results from these studies could lead to a significant paradigm shift in treatment strategies for liver cancer and other chronic inflammatory diseases if epigenetic modulation of inflammatory signaling mediated by PPAR/ is shown to effectively prevent hepatocarcinogenesis.