Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma.
Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma.
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NF-κB转录因子作为炎症和免疫应答以及细胞存活的关键调节因子发挥作用。它们也与细胞转化和肿瘤发生有关。然而，尽管在过去的二十年中对NF-κB信号传导进行了广泛的生物化学表征，但在体内肿瘤发展中，特别是在实体瘤中，对NF-κB的需求尚未完全理解。在这里，我们表明，NF-κB途径是需要在小鼠肺腺癌模型的肿瘤的发展。在原代小鼠胚胎成纤维细胞中，p53的缺失和致癌基因K-rasG 12 D的表达导致NF-κB活化。相反，在表达K-rasG 12 D且缺乏p53的肺肿瘤细胞系中，p53恢复导致NF-κB抑制。此外，抑制NF-κB信号转导可诱导p53缺失肺癌细胞系的凋亡。从肿瘤开始或肿瘤进展后，在体内抑制肺肿瘤中的通路，导致肿瘤发展显著减少。总之，这些结果表明NF-κB信号在肺肿瘤发展中的关键功能，并且进一步地，这种需求取决于p53状态。这些发现也为开发NF-κB抑制药物作为治疗K-ras和p53明确突变患者的靶向治疗提供了支持。
NF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-κB signaling during the past twenty years, the requirement for NF-κB in tumor development in vivo, particularly in solid tumors, is not completely understood. Here we show that the NF-κB pathway is required for the development of tumors in a mouse model of lung adenocarcinoma. Concomitant loss of p53 and expression of oncogenic K-rasG12D resulted in NF-κB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumor cell lines expressing K-rasG12D and lacking p53, p53 restoration led to NF-κB inhibition. Additionally, inhibition of NF-κB signaling induced apoptosis in p53 null lung cancer cell lines. Inhibition of the pathway in lung tumors in vivo, from the time of tumor initiation or following tumor progression, resulted in significantly reduced tumor development. Together, these results suggest a critical function for NF-κB signaling in lung tumor development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-κB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in K-ras and p53.