转录因子 NF-κB 家族和小 GTP 酶 Ras 家族是驱动肿瘤发生和癌变的增殖信号传导的重要介质。 κB-Ras 蛋白先前已被证明可通过独立机制抑制 NF-κB 和 Ras 激活，这表明它们作为肿瘤抑制因子，与人类癌症具有潜在广泛的相关性。在这项研究中，我们使用了两种小鼠模型来建立 κB-Ras 蛋白与肿瘤发生的相关性。此外，我们还利用泛癌生物信息学分析来探索 κB-Ras 蛋白在人类癌症中的作用。令人惊讶的是，我们发现编码 κB-Ras 1 (NKIRAS1) 和 κB-Ras 2 (NKIRAS2) 的基因在具有致癌 Ras 突变的肿瘤样本中很少下调。人类 NKIRAS1 表达的降低与至少四种癌症类型的预后较差有关，并与肿瘤发生相关的基因网络有关。我们的研究结果提供了直接证据，证明不携带致癌 RAS 突变的人类肿瘤中 NKIRAS1 的缺失与较差的临床结果相关。

The NF-κB family of transcription factors and the Ras family of small GTPases are important mediators of proproliferative signaling that drives tumorigenesis and carcinogenesis. The κB-Ras proteins were previously shown to inhibit both NF-κB and Ras activation through independent mechanisms, implicating them as tumor suppressors with potentially broad relevance to human cancers. In this study, we have used two mouse models to establish the relevance of the κB-Ras proteins for tumorigenesis. Additionally, we have utilized a pan-cancer bioinformatics analysis to explore the role of the κB-Ras proteins in human cancers. Surprisingly, we find that the genes encoding κB-Ras 1 (NKIRAS1) and κB-Ras 2 (NKIRAS2) are rarely down-regulated in tumor samples with oncogenic Ras mutations. Reduced expression of human NKIRAS1 alone is associated with worse prognosis in at least four cancer types and linked to a network of genes implicated in tumorigenesis. Our findings provide direct evidence that loss of NKIRAS1 in human tumors that do not carry oncogenic RAS mutations is associated with worse clinical outcomes.