title: CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway.
abstract: Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) are common head and neck cancers with a high propensity for lymph node (LN) and lung metastasis. Here, we report that LHSCCs express high levels of functional CXCR4 receptors, native for chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Primary tumor immunohistochemistry from LHSCC patients has revealed significant expression of CXCR4 and CXCL12. Greater expression of CXCR4 but not that of CXCL12 is correlated with LN and distant metastasis. Reverse transcription-polymerase chain reaction and western blots have demonstrated that CXCR4 messenger RNA (mRNA) and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced extracellular signal-regulated kinase (ERK) pathway activation and the motility/invasiveness of LHSCC cell lines, which were blocked by treatment with a CXCR4 antagonist (AMD3100) and a specific MEK inhibitor (U0126). Results show that the mRNA and protein levels of matrix metalloproteinase (MMP)-13, but not MMP-2 or MMP-9, were elevated in HEp-2 cells in response to CXCL12. Again, U0126 almost inhibited the induction of MMP-13 in HEp-2 cells by stimulating CXCL12. The transcriptional factor, c-Jun, a downstream factor of ERK pathway, was found to be readily phosphorylated and translocated to the nucleus after 10 min of exposure to CXCL12. Blockage of c-Jun activity by transfection with c-jun antisense oligodeoxynucleotide significantly decreased CXCL12-induced MMP-13 expression and cell invasion. CXCL12 seems to enhance LHSCC cell invasion through paracrine-activated CXCR4, which triggers ERK/c-Jun-dependent MMP-13 upregulation.
authors.affiliation: Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei 100, Taiwan.
authors.forename: Ching-Ting
authors.initials: CT
authors.lastname: Tan
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Chu
authors.forename: Ying-Chang
authors.initials: YC
authors.lastname: Lu
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chang
authors.forename: Been-Ren
authors.initials: BR
authors.lastname: Lin
authors.forename: Hsaio-Hui
authors.initials: HH
authors.lastname: Wu
authors.forename: Hsin-Ling
authors.initials: HL
authors.lastname: Liu
authors.forename: Shih-Ting
authors.initials: ST
authors.lastname: Cha
authors.forename: Ekambaranellore
authors.initials: E
authors.lastname: Prakash
authors.forename: Jenq-Yuh
authors.initials: JY
authors.lastname: Ko
authors.forename: Min-Liang
authors.initials: ML
authors.lastname: Kuo
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000235:genetics*; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000473:pathology*; D007150:Immunohistochemistry; D007822:Laryngeal Neoplasms / Q000473:pathology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D019718:Receptors, CXCR4 / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D018808:Transcription Factor AP-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053509:Matrix Metalloproteinase 13