NF-κB Signaling Pathway Confers Neuroblastoma Cells Migration and Invasion Ability via the Regulation of CXCR4
Yunlai Zhi, Yuhe Duan, Xianjun Zhou, Xiaofeng Yin, Ge Guan, Hong Zhang, Qian Dong, Kun Yang
Department of Pediatric Surgery, Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
Med Sci Monit 2014; 20:2746-2752
Accumulating evidence implicates the transcription factor NF-κB as a positive mediator of tumor metastasis, but the molecular mechanism(s) involved in this process remains largely unknown. In this study, we investigated the role of NF-κB signaling pathway in the regulation of CXC chemokine receptor-4 (CXCR4) in neuroblastoma metastasis.
Material and Methods: NF-κB, CXCR4 mRNA and protein expression were measured by RT-PCR, and Western blot. Tumor necrosis factor-α (TNF-α) was used to induce the upregulation of NF-κB and CXCR4. The knockdown of NF-κB and CXCR4 was achieved by PDTC. Transwell assay was used to investigate the role of NF-κB (P65) in neuroblastoma cell migration and invasion. An in vitro co-culture system was established to investigate the role of tumor microenvironment in regulation of the NF-κB signaling pathway.
Results: Over-expression of NF-κB (p65) promoted tumor migration and invasion through the upregulation of CXCR4; however, knockdown of NF-κB(P65) inhibited tumor migration and invasion through blocking the expression of CXCR4. Consistently, in the co-culture system, the expression of CXCR4 was partly dependent on the expression of NF-κB (p65).
Conclusions: Our studies reveal critical roles for the NF-κB signaling pathway in neuroblastoma migration and invasion. The mechanism may be through up-regulation of CXCR4, mediated by the NF-κB signaling pathways. Targeting NF-κB signalling pathways and ultimately CXCR4 could be a strategy in neuroblastoma therapy.
Keywords: Cell Line, Tumor, Brain Neoplasms - pathology, Cell Movement - drug effects, Chemokine CXCL12 - pharmacology, Coculture Techniques, Macrophages - metabolism, NF-kappa B - metabolism, Neoplasm Invasiveness, Neuroblastoma - pathology, Receptors, CXCR4 - metabolism, Signal Transduction - drug effects, Up-Regulation