文章：

过氧化物酶体增殖物激活受体在癌变和化学预防中的作用

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention

原文发布日期：2012-02-09

DOI: 10.1038/nrc3214

类型: Review Article

开放获取: 否

要点：

1. Peroxisome proliferator-activated receptors (PPARs) have central roles in the regulation of glucose and lipid homeostasis through their functions as molecular sensors that respond to endogenous ligands, leading to the modulation of gene expression. PPARs also regulate cell proliferation, differentiation and inflammation.
2. PPARα mediates hepatocarcinogenesis induced by long-term administration of PPARα agonists in rodent models, an effect that is not found in humans. The mechanism underlying species-specific hepatocarcinogenesis is through mouse PPARα-dependent regulation of the let-7c microRNA, which leads to increased expression of the oncoprotein MYC. The current interest in targeting PPARα for the prevention of certain cancers, including colon and leukaemia, is based on studies showing that PPARα agonists inhibit the proliferation of endothelial cells, increase the synthesis of PPARγ agonists and potentially interfere with the Warburg effect.
3. The role of PPARβ/δ in carcinogenesis is controversial. Several studies have shown that PPARβ/δ is upregulated in cancer cells by the adenomatous polyposis coli (APC)–β-catenin–TCF4 pathway and has a pro-tumorigenic effect in many cancer types. However, other studies have shown that PPARβ/δ agonists can induce terminal differentiation and inhibit innate inflammation, suggesting anticancer effects. In addition, a retrospective study has shown that low expression levels of PPARβ/δ are associated with the decreased survival of patients with colorectal cancer. Therefore, there remains a need to further examine PPARβ/δ protein expression patterns quantitatively in tumour models and the putative mechanisms that are mediated by PPARβ/δ agonists associated with anti-apoptotic or growth stimulatory effects.
4. PPARγ agonists can induce terminal differentiation, inhibit cell proliferation, promote apoptosis and inhibit innate inflammation in many cancer models. This has led to a number of clinical trials with PPARγ agonists, but these have generated mixed results. Moreover, some PPARγ agonists have been associated with pro-tumorigenic effects. Emerging evidence indicates that targeting PPARγ in combination with other chemopreventive or chemotherapeutic agents might increase the efficacy of the effects that are induced by monotherapies.
5. Owing to similarities in the abilities of the three PPARs to improve different metabolic disorders that are known to be associated with increased cancer risk (such as diabetes, obesity, dyslipidemias and chronic inflammation), modulating the activities of the PPARs remains an attractive approach for the treatment and prevention of cancer. The challenge is to advance the discovery of molecular mechanisms of action in order to identify and characterize effective PPAR agonists with acceptable safety profiles.

要点翻译：

1. 过氧化物酶体增殖物激活受体（PPARs）通过其作为分子传感器的功能，在调节葡萄糖和脂质稳态中发挥核心作用。它们能够响应内源性配体，进而调控基因表达。PPARs还参与调节细胞增殖、分化和炎症反应。
2. 在啮齿类动物模型中，长期给予PPARα激动剂会通过PPARα介导肝细胞癌发生，但这种效应在人类中并未发现。物种特异性肝细胞癌发生的机制在于小鼠PPARα依赖性调控let-7c微RNA，从而导致癌蛋白MYC表达增加。目前针对PPARα预防某些癌症（包括结肠癌和白血病）的研究兴趣，基于多项研究表明PPARα激动剂能抑制内皮细胞增殖、增加PPARγ激动剂的合成，并可能干扰Warburg效应。
3. PPARβ/δ在致癌作用中的角色存在争议。多项研究显示，PPARβ/δ通过腺瘤性息肉病大肠杆菌（APC）-β-连环蛋白-TCF4通路上调癌细胞表达，在多种癌症类型中发挥促肿瘤发生作用。然而其他研究表明，PPARβ/δ激动剂可诱导终末分化并抑制先天炎症，提示其具有抗癌效应。此外，一项回顾性研究显示，PPARβ/δ低表达与结直肠癌患者生存率降低相关。因此，仍需在肿瘤模型中定量研究PPARβ/δ蛋白表达模式，并深入探究PPARβ/δ激动剂介导抗凋亡或生长刺激效应的潜在机制。
4. 在多种癌症模型中，PPARγ激动剂可诱导终末分化、抑制细胞增殖、促进细胞凋亡并抑制先天炎症。这推动了多项PPARγ激动剂的临床试验，但结果良莠不齐。更有研究发现部分PPARγ激动剂具有促肿瘤发生效应。新证据表明，将PPARγ靶向治疗与其他化学预防或化疗药物联用，可能增强单药治疗的疗效。
5. 由于三种PPAR亚型在改善多种已知与癌症风险增加相关的代谢紊乱（如糖尿病、肥胖、血脂异常和慢性炎症）方面具有相似功能，调控PPAR活性仍是癌症治疗和预防的重要策略。当前挑战在于深入探索其分子作用机制，以鉴定和表征具有可接受安全性的高效PPAR激动剂。

英文摘要：

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs that are used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

摘要翻译： 

过氧化物酶体增殖物激活受体（PPARs）是配体激活的转录因子，参与调节葡萄糖和脂质稳态、炎症、增殖与分化。尽管这些功能都可能影响PPARs在致癌过程中的作用，但仍需通过文献综述和进一步实验，明确将PPARs作为癌症治疗和化学预防靶点的潜力。由于PPAR激动剂中包含用于治疗代谢性疾病的药物，更全面地了解PPARs在癌症中的作用，有助于评估接受PPAR激动剂治疗的患者是否存在增加的癌症风险。

原文链接：

The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention