Abstract
BackgroundNF-κB signaling pathway plays an important role in gastric carcinogenesis. The basic expression and functional role of NFKB1 and RELA (components of canonical NF-κB pathway) in gastric cancer (GC) have not been well elucidated. In this study, the role of NFKB1 and RELA in gastric tumorigenesis will be investigated and their regulation by microRNAs (miRNAs) will be deeply explored.MethodsThe mRNA and protein expression of NFKB1 and RELA were investigated by qRT-PCR and Western blot in GC cell lines and primary tumors. The functional roles of NFKB1 and RELA in GC were demonstrated by MTT proliferation assay, monolayer colony formation, cell invasion and migration, cell cycle analysis and in vivo study through siRNA mediated knockdown. Identification of NFKB1 as a direct target of tumor suppressor miRNA miR-508-3p was achieved by expression regulation assays together with dual luciferase activity experiments.ResultsNFKB1 and RELA were up-regulated in GC cell lines and primary tumors compared with normal gastric epithelium cells and their upregulation correlation with poor survival in GC. siRNA mediated knockdown of NFKB1 or RELA exhibited anti-oncogenic effect both in vitro and in vivo. NFKB1 was further revealed to be a direct target of miR-508-3p in gastric tumorigenesis and their expression showed negative correlation in primary GC samples. miR-508-3p was down-regulated in GC cells compared with normal gastric epithelium samples and its ectopic expression in GC cell lines also exerts tumor suppressor function. NFKB1 re-expression was found to partly abolish the tumor-suppressive effect of miR-508-3p in GC.ConclusionAll these findings supports that canonical NF-κB signaling pathway is activated in GC at least by the inactivation of miR-508-3p and this might have therapeutic potential in GC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0493-7) contains supplementary material, which is available to authorized users.
Highlights
nuclear factor-kappa B (NF-κB) signaling pathway plays an important role in gastric carcinogenesis
NF-κB is reported to play an important role in the induction of cytokine expression and promote progression of gastric cancer (GC) [11], and its activation correlates with chronic inflammation and tumorigenesis induced by H. pylori for gastric tumor [12, 13]
We found that NFKB1 and RELA protein levels were upregulated but there are no significant differences between normal control and cancerous tissues from mRNA expression, suggesting the translational or post-translational regulation play important role for the upregulated protein expression of NF-κB
Summary
NF-κB signaling pathway plays an important role in gastric carcinogenesis. The basic expression and functional role of NFKB1 and RELA (components of canonical NF-κB pathway) in gastric cancer (GC) have not been well elucidated. Mammalian NF-κB family is composed of five members, including RELA ( named p65), RELB, c-Rel, NF-κB1 p50, and NF-κB2 p52, which form various dimeric complexes that transactivates numerous target genes via binding to the κB enhancer [6] These proteins function as dimeric transcription factors that control genes regulating a broad range of biological processes including inflammation and cancer [7,8,9]. We found that NFKB1 and RELA protein (key components of canonical NF-κB pathway) levels were upregulated but there are no significant differences between normal control and cancerous tissues from mRNA expression, suggesting the translational or post-translational regulation play important role for the upregulated protein expression of NF-κB
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