Meta-Analysis Identifies NF-κB as a Therapeutic Target in Renal Cancer

Objective
To determine the expression patterns of NF-κB regulators and target genes in clear cell renal cell carcinoma (ccRCC), their correlation with von Hippel Lindau (VHL) mutational status, and their association with survival outcomes.
Methods
Meta-analyses were carried out on published ccRCC gene expression datasets by RankProd, a non-parametric statistical method. DEGs with a False Discovery Rate of < 0.05 by this method were considered significant, and intersected with a curated list of NF-κB regulators and targets to determine the nature and extent of NF-κB deregulation in ccRCC.
Results
A highly-disproportionate fraction (~40%; p < 0.001) of NF-κB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-κB activity in this cancer. A subset of these genes, comprising a key NF-κB regulator (IKBKB) and established mediators of the NF-κB cell-survival and pro-inflammatory responses (MMP9, PSMB9, and SOD2), correlated with higher relative risk, poorer prognosis, and reduced overall patient survival. Surprisingly, levels of several interferon regulatory factors (IRFs) and interferon target genes were also elevated in ccRCC, indicating that an ‘interferon signature’ may represent a novel feature of this disease. Loss of VHL gene expression correlated strongly with the appearance of NF-κB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-κB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-κB activity, and the appearance of an interferon signature during ccRCC tumorigenesis.
Conclusions
These findings identify NF-κB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-κB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-κB targets for potential therapeutic intervention in this currently-incurable malignancy.

**研究目标** 明确核因子κB（NF-κB）调控因子与靶基因在透明细胞肾细胞癌（clear cell renal cell carcinoma, ccRCC）中的表达模式，及其与希佩尔-林道（von Hippel Lindau, VHL）突变状态的相关性，以及与患者生存结局的关联。
**研究方法** 采用非参数统计方法RankProd，对已发表的ccRCC基因表达数据集开展荟萃分析。以该方法筛选得到的错误发现率（False Discovery Rate, FDR）<0.05的差异表达基因（differentially expressed genes, DEGs）判定为具有统计学意义的显著差异基因，并与经人工整理注释的NF-κB调控因子及靶基因列表取交集，以明确ccRCC中NF-κB失调的性质与程度。
**研究结果** 研究发现，约40%（p<0.001）的NF-κB调控因子与靶基因在ccRCC中呈上调表达，提示该恶性肿瘤中NF-κB活性升高。其中部分基因包含关键NF-κB调控因子IKBKB，以及已被证实的NF-κB细胞存活与促炎反应介导因子MMP9、PSMB9和SOD2，这些基因与更高的相对风险、更差的预后以及更短的患者总生存期显著相关。令人意外的是，多种干扰素调节因子（interferon regulatory factors, IRFs）及干扰素靶基因在ccRCC中的表达水平也显著升高，表明「干扰素特征」可能是该疾病的全新临床特征。VHL基因表达缺失与家族性和散发性ccRCC病例中NF-κB及干扰素基因特征的出现均呈显著相关。由于NF-κB可调控关键干扰素信号节点的表达，本研究结果提示，在ccRCC肿瘤发生过程中，VHL缺失、NF-κB活性升高与干扰素特征的出现之间存在因果关联。
**研究结论** 本研究结果明确了NF-κB与干扰素特征可作为ccRCC的临床特征，为在ccRCC治疗中应用NF-κB抑制剂或靶向干扰素信号通路提供了坚实的理论依据，并为这种目前尚无法治愈的恶性肿瘤提供了新的NF-κB潜在治疗靶点。