Carcinogenesis Advance Access originally published online on May 16, 2008
Carcinogenesis 2008 29(8):1519-1527; doi:10.1093/carcin/bgn108
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CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway
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1 Department of Otolaryngology
2 Department of Dermatology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei 100, Taiwan
3 Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine and Angiogenesis Research Center, National Taiwan University, Taipei 100, Taiwan
* To whom correspondence should be addressed. Tel: +886 2 23123456 ext. 5222; Fax: +886 2 2341 0905; Email: jyko{at}ntu.edu.tw
Correspondence may also be addressed to Min-Liang Kuo. Tel: +886 2 2312 3456 ext. 8607; Fax: +886 2341 0217; Email: kuominliang{at}ntu.edu.tw
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.
Abbreviations: AP, activator protein; ERK, extracellular signal-regulated kinase; HNSCC, head and neck squamous cell carcinoma; LHSCC, laryngeal and hypopharyngeal squamous cell carcinoma; LN, lymph node; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; OSCC, oral squamous cell carcinoma; PCR, polymerase chain reaction; P13K, phosphatidylinositol-3 kinase; SCC, squamous cell carcinoma
These authors contributed equally to this work. Received December 11, 2007; revised April 25, 2008; accepted April 29, 2008.