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

Abstract

ObjectiveTo 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.MethodsMeta-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.ResultsA 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.ConclusionsThese 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.

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…Indeed, gene expression studies in large cohorts of RCC-bearing patients have suggested that some molecules such as IL-1, IL-6, TNF-α, C1q, and C1r could be implicated in the initiation and promotion of an intratumor inflammatory cascade (Peri, Devarajan, Yang, Knudson, & Balachandran, 2013;Romero et al, 2006;Tan et al, 2011). The RCC tumor cells probably orchestrate this inflammatory environment as suggested by the presence of several cytokines in the supernatant of RCC primary cultures, including IL-8, IL-10, TGF-β, GM-CSF, TNF-α, and VEGF (Gogusev, Augusti, Chrétien, & Droz, 1993;Knoefel et al, 1997;Lahn et al, 1999;Lee, Chun, Nadiminty, Lou, & Gao, 2007;Sievers et al, 2007).…”

Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

“…Oncogenesis does not follow a strict pattern of signal relay, and is not confined to a single cell source, even if gene expression follows certain lineage-dependent restrictions. However, analysis of gene expression gives information on the NF-κB target gene signature that is essential to identify critical downstream pharmacological therapeutic targets [64]. When combined with the study of cultured cells, genetic analysis enables a personalized approach to tumors unforeseen by standard therapeutic protocols [65].…”

Identification of immunohistochemical biomarkers that differentiate chromophobe renal cell carcinoma from renal oncocytoma through molecular profiling of renal tumours

“…With respect to RCC cancer overall survival, a recent meta-analysis on clear cell RCC gene expression identified 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 (Peri et al 2013). In comparison, some have reported that NF-κB was not a prognostic factor in RCC survival (Kankaya et al 2015;Sourbier et al 2007).…”

“…Studies showed that p65 expression is upregulated and constitutively activated in RCC tissue (Djordjevic et al 2008;Peri et al 2013). NF-κB p65 and p50 have both been correlated with apoptotic and proliferation markers in RCC tissue (Kankaya et al 2015).…”

“…However, the prognostic implications of NF-κB in RCC are contradictory, based on previous research where NF-κB was associated with poorer prognosis (Oya et al 2003;Peri et al 2013;Djordjevic et al 2008) while others did not correlate NF-κB with survival or prognosis (Kankaya et al 2015;Meteoglu et al 2008;;Sourbier et al 2007). Currently to our knowledge, there is no published literature on NF-κB2 (p100/p52), RelB and c-Rel expression in human RCC and their prognostic value.…”