title: Involvement of the nuclear factor-κB signaling pathway in the regulation of CXC chemokine receptor-4 expression in neuroblastoma cells induced by tumor necrosis factor-α.
abstract: Metastasis is a hallmark of malignant neuroblastoma and is the main reason for therapeutic failure and recurrence of the tumor. The CXC chemokine receptor-4 (CXCR4), a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1α (SDF-1α), is expressed in various types of tumor. This receptor mediates the homing of tumor cells to specific organs that express the ligand, CXCL12, for this receptor and plays an important role in tumor growth, invasion, metastasis and angiogenesis. In the present study, the inflammatory cytokine, tumor necrosis factor‑α (TNF‑α) upregulated CXCR4 expression in neuroblastoma cells and increased migration to the CXCR4 ligand SDF‑1α. In addition, this effect was dependent upon NF-κB transcriptional activity, as blocking the NF-κB pathway with pyrrolidinedithiocarbamic acid ammonium salt suppressed TNF-α‑induced upregulation of CXCR4 expression and reduced the migration towards the CXCR4 ligand, SDF-1α. Treating neuroblastoma cells with TNF-α resulted in the activation of nuclear factor-kappa B (NF-κB) and subsequently, the translocation of NF-κB from the cytoplasm to the nucleus. Using immunohistochemistry, NF‑κB and CXCR4 were significantly correlated with each other (P=0.0052, Fisher's exact test) in a cohort of neuroblastoma samples (n=80). The present study indicates that the inflammatory cytokine, TNF-α, partially functions through the NF‑κB signaling pathway to upregulate CXCR4 expression to foster neuroblastoma cell metastasis. These findings indicate that effective inhibition of neuroblastoma metastasis should be directed against the inflammatory cytokine-induced NF‑κB/CXCR4/SDF‑1α signaling pathway.
authors.affiliation: Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.
authors.forename: Yunlai
authors.initials: Y
authors.lastname: Zhi
authors.affiliation: Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.
authors.forename: Hongting
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.
authors.forename: Yuhe
authors.initials: Y
authors.lastname: Duan
authors.affiliation: Department of Pediatric Surgery, The Children's Hospital of Zhengzhou, Henan 450053, P.R. China.
authors.forename: Weisheng
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao 266003, P.R. China.
authors.forename: Ge
authors.initials: G
authors.lastname: Guan
authors.affiliation: Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Pediatric Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.
authors.forename: Chuanmin
authors.initials: C
authors.lastname: Yang
mesh_terms: D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007223:Infant; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; D014409:Tumor Necrosis Factor-alpha