title: NF-κB participates in chemokine receptor 7-mediated cell survival in metastatic squamous cell carcinoma of the head and neck.
abstract: Metastatic squamous cell carcinoma of the head and neck (SCCHN) has been shown to express chemokine receptor 7 (CCR7), which activates phosphoinositide-3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signal pathway to promote the invasion and survival of SCCHN cells. Since nuclear factor-kappa B (NF-κB) is shown to be the downstream signal molecule of PI3K/Akt in many tumors, we investigated whether it also exists in the CCR7 pathway in SCCHN, and the relationship between NF-κB and PI3K/Akt/mTOR, and the role it plays in SCCHN. We assayed the phosphorylation of the inhibitor of NF-κB (IκBα), the NF-κB DNA-binding capacity and location. The results showed that the interaction between CCR7 and the ligand for CCR7, CCL19, induces phosphorylation of IκBα, causes NF-κB to translocate to the nucleus and raises the DNA-binding capacity of NF-κB. The phosphorylation and DNA-binding capacity were abolished by the inhibition of CCR7, PI3K, Akt and mTOR. Further research demonstrated that inhibitors of NF-κB and CCR7-PI3K attenuate the survival of CCR7-mediated cells, causing decreased viability, increased apoptosis and increased cell cycle arrest in SCCHN cells. In clinical samples from 78 patients, immunohistochemical assay also showed that CCR7 and NF-κB are not only highly expressed in SCCHN, but also correlated with each other, and related to lymph node metastasis and clinical stage. Together, our data indicate that NF-κB is activated by CCR7 via PI3K/Akt/mTOR, and this signal pathway plays an important role in regulating the cell survival and prognosis of SCCHN.
authors.affiliation: Department of Oromaxillofacial-Head and Neck Surgery, School of Stomatology, China Medical University, No. 117, Nanjing Bei Jie, Heping District, Shenyang, Liaoning 110002, PR China.
authors.forename: Fa-Yu
authors.initials: FY
authors.lastname: Liu
authors.forename: Zhen-Jin
authors.initials: ZJ
authors.lastname: Zhao
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Xue
authors.initials: X
authors.lastname: Ding
authors.forename: Nan
authors.initials: N
authors.lastname: Guo
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Yang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Zong
authors.forename: Chang-Fu
authors.initials: CF
authors.lastname: Sun
mesh_terms: D002277:Carcinoma / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002470:Cell Survival; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D009362:Neoplasm Metastasis; D018307:Neoplasms, Squamous Cell / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D054387:Receptors, CXCR / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000077195:Squamous Cell Carcinoma of Head and Neck; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054387:Receptors, CXCR; D058570:TOR Serine-Threonine Kinases; C501896:ACKR3 protein, human; C546842:MTOR protein, human