title: The independent, unfavorable prognostic factors endothelin A receptor and chemokine receptor 4 have a close relationship in promoting the motility of nasopharyngeal carcinoma cells via the activation of AKT and MAPK pathways.
abstract: BACKGROUND
  Recent studies have indicated that the expression of endothelin A receptor (ETAR) and chemokine receptor 4 (CXCR4) could be used as an indicator of the metastatic potential of nasopharyngeal carcinoma (NPC). The aim of this study was to determine the prognostic value of ETAR and CXCR4 in NPC patients and to reveal the interplay of the endothelin-1 (ET-1)/ETAR and stromal-derived factor-1(SDF-1)/CXCR4 pathways in promoting NPC cell motility.
  
  
  METHODS
  Survival analysis was used to analyze the prognostic value of ETAR and CXCR4 expression in 153 cases of NPC. Chemotaxis assays were used to evaluate alterations in the migration ability of non-metastatic 6-10B and metastatic 5-8F NPC cells. Real-time PCR, immunoblotting, and flow cytometric analyses were used to evaluate changes in the expression levels of CXCR4 mRNA and protein induced by ET-1.
  
  
  RESULTS
  The expression levels of ETAR and CXCR4 were closely related to each other and both correlated with a poor prognosis. A multivariate analysis showed that the expression levels of both ETAR and CXCR4 were independent prognostic factors for overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The migration of 6-10B and 5-8F cells was elevated by ET-1 in combination with SDF-1α. The knockdown of ETAR protein expression by siRNA reduced CXCR4 protein expression in addition to ETAR protein expression, leading to a decrease in the metastatic potential of the 5-8F cells. ET-1 induced CXCR4 mRNA and protein expression in the 6-10B NPC cells in a time- and concentration-dependent fashion and was inhibited by an ETAR antagonist and PI3K/AKT/mTOR and MAPK/ERK1/2 pathway inhibitors.
  
  
  CONCLUSIONS
  ETAR and CXCR4 expression levels are potential prognostic biomarkers in NPC patients. ETAR activation partially promoted NPC cell migration via a mechanism that enhanced functional CXCR4 expression.
authors.affiliation: State Key Laboratory of Oncology in South China, Guangzhou, Guangdong 510060, P, R, China. maihq@sysucc.org.cn.
authors.forename: Dong-Hua
authors.initials: DH
authors.lastname: Luo
authors.forename: Qiu-Yan
authors.initials: QY
authors.lastname: Chen
authors.forename: Huai
authors.initials: H
authors.lastname: Liu
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Xu
authors.forename: Hui-Zhong
authors.initials: HZ
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Lin-Quan
authors.initials: LQ
authors.lastname: Tang
authors.forename: Hao-Yuan
authors.initials: HY
authors.lastname: Mo
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Huang
authors.forename: Xiang
authors.initials: X
authors.lastname: Guo
authors.forename: Hai-Qiang
authors.initials: HQ
authors.lastname: Mai
mesh_terms: D002277:Carcinoma; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000235:genetics; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019332:Endothelin-1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044022:Receptor, Endothelin A; D019718:Receptors, CXCR4; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases