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Peri S , Devarajan K , Yang DH , Knudson AG , Balachandran S
Meta-Analysis Identifies NF-kappaB as a Therapeutic Target in Renal Cancer
PLoS One. 2013 ;8(10) :e76746
PMID: 24116146   
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OBJECTIVE: To determine the expression patterns of NF-kappaB 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-kappaB regulators and targets to determine the nature and extent of NF-kappaB deregulation in ccRCC. RESULTS: A highly-disproportionate fraction (~40%; p < 0.001) of NF-kappaB regulators and target genes were found to be up-regulated in ccRCC, indicative of elevated NF-kappaB activity in this cancer. A subset of these genes, comprising a key NF-kappaB regulator (IKBKB) and established mediators of the NF-kappaB 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-kappaB- and interferon gene signatures in both familial and sporadic cases of ccRCC. As NF-kappaB controls expression of key interferon signaling nodes, our results suggest a causal link between VHL loss, elevated NF-kappaB activity, and the appearance of an interferon signature during ccRCC tumorigenesis. CONCLUSIONS: These findings identify NF-kappaB and interferon signatures as clinical features of ccRCC, provide strong rationale for the incorporation of NF-kappaB inhibitors and/or and the exploitation of interferon signaling in the treatment of ccRCC, and supply new NF-kappaB targets for potential therapeutic intervention in this currently-incurable malignancy.
Peri, Suraj Devarajan, Karthik Yang, Dong-Hua Knudson, Alfred G Balachandran, Siddharth United States PloS one PLoS One. 2013 Oct 7;8(10):e76746. doi: 10.1371/journal.pone.0076746.