Lyon Cancer Research Center, University Claude Bernard Lyon1, INSERM U1052 - CNRS UMR5286, Centre Leon Berard, Lyon, France.
Curr Opin Oncol. 2014 Jan;26(1):86-91. doi: 10.1097/CCO.0000000000000037.
Inflammation is emerging as a new hallmark of cancer, and the toll-like receptor and interleukin-1 receptor adaptor molecule MyD88 has been linked to tumorigenesis. The purpose of this review is to give a brief overview of the latest advances in understanding the complexity of MyD88 implication in tumorigenesis.
MyD88 is shown to play a protumorigenic role through two mechanisms. First, it activates the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway in the hematopoietic compartment and in tumor cells, inducing an inflammatory environment favorable to carcinogenesis. Second, it plays a cell-autonomous role in Ras signaling and transformation, independently of its role in inflammatory signaling. MyD88 mediates the optimal activation of the Ras/extracellular signal-regulated kinase (ERK) pathway by binding to ERK and protecting it from dephosphorylation. This optimal activation of the Ras pathway is essential for the expression of important DNA repair enzymes, allowing cancer cells to efficiently repair damaged DNA. MyD88 is also shown in certain cases to play an antitumoral role through modulation of the immune response
These findings present a new dual function model for MyD88 implication in carcinogenesis making it a potential therapeutic target in cancer.
炎症正在成为癌症的一个新标志， Toll 样受体和白细胞介素-1 受体衔接分子 MyD88 与肿瘤发生有关。本综述的目的是简要概述理解 MyD88 在肿瘤发生中的复杂性的最新进展。
MyD88 通过两种机制发挥致癌作用。首先，它在造血细胞和肿瘤细胞中激活核因子 kappa 轻链增强子激活 B 细胞信号通路，诱导有利于致癌的炎症环境。其次，它在 Ras 信号和转化中发挥自主作用，而不依赖于其在炎症信号中的作用。MyD88 通过与 ERK 结合并保护其免于去磷酸化，介导 Ras/细胞外信号调节激酶 (ERK) 通路的最佳激活。这种 Ras 通路的最佳激活对于表达重要的 DNA 修复酶是必需的，使癌细胞能够有效地修复受损的 DNA。在某些情况下，MyD88 通过调节免疫反应也表现出抗肿瘤作用。
这些发现提出了 MyD88 在致癌作用中的新的双重功能模型，使其成为癌症治疗的潜在靶点。
