CNRS UMR5201, University of Lyon, Centre Léon Bérard, Lyon, France.
J Clin Invest. 2010 Oct;120(10):3663-7. doi: 10.1172/jci42771.
Accumulating evidence points to inflammation as a promoter of carcinogenesis. MyD88 is an adaptor molecule in TLR and IL-1R signaling that was recently implicated in tumorigenesis through proinflammatory mechanisms. Here we have shown that MyD88 is also required in a cell-autonomous fashion for RAS-mediated carcinogenesis in mice in vivo and for MAPK activation and transformation in vitro. Mechanistically, MyD88 bound to the key MAPK, Erk, and prevented its inactivation by its phosphatase, MKP3, thereby amplifying the activation of the canonical RAS pathway. The relevance of this mechanism to human neoplasia was suggested by the finding that MyD88 was overexpressed and interacted with activated Erk in primary human cancer tissues. Collectively, these results show that in addition to its role in inflammation, MyD88 plays what we believe to be a crucial direct role in RAS signaling, cell-cycle control, and cell transformation.
越来越多的证据表明炎症是致癌的促进因素。MyD88 是 TLR 和 IL-1R 信号转导中的衔接分子，最近通过炎症机制被牵连到肿瘤发生中。在这里，我们已经表明，MyD88 还以细胞自主的方式在体内 RAS 介导的致癌作用以及体外 MAPK 激活和转化中是必需的。从机制上讲，MyD88 与关键的 MAPK，Erk 结合，并阻止其磷酸酶 MKP3 使其失活，从而放大了经典 RAS 途径的激活。MyD88 在原发性人类癌症组织中过度表达并与激活的 Erk 相互作用，这表明该机制与人类肿瘤发生有关。总之，这些结果表明，除了在炎症中的作用外，MyD88 在 RAS 信号转导、细胞周期控制和细胞转化中还发挥着我们认为至关重要的直接作用。
