Long non-coding RNAs (IncRNAs) is a large class of RNA molecules involved in a variety of biological processes.Presently,only a small number of IncRNAs have been characterized to control gene expression as decoys, guides or scaffolds mainly in the nuclei to interact with DNA, RNA or gene-regulatory proteins.However, the roles of many IncRNAs located in cytoplasm are unknown.We demonstrated that expression of cytoplasmic NF-κB interacting IncRNA (NKILA) is up-regulated in breast cancer cells by inflammatory stimuli through NF-κB signaling.Further, silencing NKILA in presence of inflammatory stimuli promotes inflammation-induced NF-κB activation, leading to enhanced EMT and reduced apoptosis in tumor cells and increased cancer metastasis in vivo.Additionally, ectopic NKILA expression inhibits NF-κB activation and the ensuing cancer invasion and metastasis, suggesting that NKILA is a negative regulator of NF-κB signaling.Indeed, NKILA prevents activation of NF-κB by interacting with the NF-κB complex in cytoplasm and inhibits IKK-induced phosphorylation and degradation of IκB.We identified the 5-region of NKILA to harbor mimicry of NF-κB binding motif that interacts directly with NF-κB p65.Moreover, the 3-region of the p65-engaged NKILA directly masks the phosphorylation motif of IκB to block its phosphorylation by IKK.These findings indicate a new mechanism by which cytoplasmic IncRNAs directly regulate activation of major signaling molecules and participate in auto-regulatory feedback circuitry of signaling pathways in cancer cells, thus uncovering a crosstalk between IncRNAs and signaling molecules that underlie cancer-related inflammation.