DRCI, Hôpital Foch, Suresnes, France.
Centre de Recherche Clinique, Grand Hôpital de l'Est Francilien (GHEF), Meaux, France.
Front Immunol. 2018 Apr 13;9:745. doi: 10.3389/fimmu.2018.00745. eCollection 2018.
Inflammation and oxidative stress are common and co-substantial pathological processes accompanying, promoting, and even initiating numerous cancers. The canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARγ) generally work in opposition. If one of them is upregulated, the other one is downregulated and . WNT/β-catenin signaling is upregulated in inflammatory processes and oxidative stress and in many cancers, although there are some exceptions for cancers. The opposite is observed with PPARγ, which is generally downregulated during inflammation and oxidative stress and in many cancers. This helps to explain in part the opposite and unidirectional profile of the canonical WNT/β-catenin signaling and PPARγ in these three frequent and morbid processes that potentiate each other and create a vicious circle. Many intracellular pathways commonly involved downstream will help maintain and amplify inflammation, oxidative stress, and cancer. Thus, many WNT/β-catenin target genes such as c-Myc, cyclin D1, and HIF-1α are involved in the development of cancers. Nuclear factor-kappaB (NFκB) can activate many inflammatory factors such as TNF-α, TGF-β, interleukin-6 (IL-6), IL-8, MMP, vascular endothelial growth factor, COX2, Bcl2, and inducible nitric oxide synthase. These factors are often associated with cancerous processes and may even promote them. Reactive oxygen species (ROS), generated by cellular alterations, stimulate the production of inflammatory factors such as NFκB, signal transducer and activator transcription, activator protein-1, and HIF-α. NFκB inhibits glycogen synthase kinase-3β (GSK-3β) and therefore activates the canonical WNT pathway. ROS activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling in many cancers. PI3K/Akt also inhibits GSK-3β. Many gene mutations of the canonical WNT/β-catenin pathway giving rise to cancers have been reported (CTNNB1, AXIN, APC). Conversely, a significant reduction in the expression of PPARγ has been observed in many cancers. Moreover, PPARγ agonists promote cell cycle arrest, cell differentiation, and apoptosis and reduce inflammation, angiogenesis, oxidative stress, cell proliferation, invasion, and cell migration. All these complex and opposing interactions between the canonical WNT/β-catenin pathway and PPARγ appear to be fairly common in inflammation, oxidative stress, and cancers.
炎症和氧化应激是常见的、共同的病理过程，伴随、促进甚至引发许多癌症。经典的 WNT/β-连环蛋白途径和过氧化物酶体增殖物激活受体γ（PPARγ）通常作用相反。如果其中一个上调，另一个就会下调。WNT/β-连环蛋白信号在炎症和氧化应激以及许多癌症中上调，尽管癌症也有一些例外。相反，PPARγ在炎症和氧化应激以及许多癌症中通常下调。这部分解释了经典的 WNT/β-连环蛋白信号和 PPARγ 在这三个经常发生且病态的相互促进并形成恶性循环的过程中的相反和单向特征。许多常见的下游细胞内途径有助于维持和放大炎症、氧化应激和癌症。因此，许多 WNT/β-连环蛋白靶基因，如 c-Myc、cyclin D1 和 HIF-1α，参与癌症的发展。核因子-κB（NFκB）可以激活许多炎症因子，如 TNF-α、TGF-β、白细胞介素-6（IL-6）、IL-8、MMP、血管内皮生长因子、COX2、Bcl2 和诱导型一氧化氮合酶。这些因子通常与癌症过程相关，甚至可能促进其发展。细胞改变产生的活性氧（ROS）刺激 NFκB、信号转导和转录激活剂、激活蛋白-1 和 HIF-α等炎症因子的产生。NFκB 抑制糖原合酶激酶-3β（GSK-3β），从而激活经典的 WNT 途径。ROS 在许多癌症中激活磷脂酰肌醇 3 激酶/蛋白激酶 B（PI3K/Akt）信号。PI3K/Akt 也抑制 GSK-3β。许多导致癌症的经典 WNT/β-连环蛋白途径基因突变已被报道（CTNNB1、AXIN、APC）。相反，许多癌症中 PPARγ 的表达显著降低。此外，PPARγ 激动剂促进细胞周期停滞、细胞分化和凋亡，并减少炎症、血管生成、氧化应激、细胞增殖、侵袭和细胞迁移。经典的 WNT/β-连环蛋白途径和 PPARγ 之间的所有这些复杂而相反的相互作用似乎在炎症、氧化应激和癌症中相当常见。
