Carcinogenesis Advance Access published online on May 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn108
CXCL12/CXCR4 promotes laryngeal and hypopharyngeal squamous cell carcinoma metastasis through MMP-13-dependent invasion via the ERK1/2/AP-1 pathway
1 Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
2 Department of Dermatology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
3 Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine & Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan
Correspondence: Jenq-Yu Ko and Min-Liang Kuo, Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, No.7, Chung-Shan South Road, Taipei 100, Taiwan. E-mail: jyko{at}ntu.edu.tw. Fax: +886-2-2341-0905. Telephone: +886-2-23123456 ext. 5222
Laryngeal and hypopharyngeal squamous cell carcinomas (LHSCC) are common head and neck cancers with a high propensity for lymph node 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 lymph node and distant metastasis. Reverse transcriptase-PCR and Western blots have demonstrated that CXCR4 mRNA and protein were expressed in LHSCC cell lines as well, but failed to detect CXCL12 mRNA expression. CXCL12 treatment enhanced 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 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 (ODN) 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 up regulation.
Key Words: CXCR4 • CXCL12 • MMP-13 • laryngeal and hypopharyngeal squamous cell carcinomas, signal transduction
Grant support: National Science Council of Taiwan (NSC 93-2314-B-002-110, NSC 94-2314-B-002-242, NSC 95-2314-B-002-177) and National Taiwan University Hospital (NTUH 95M06) (C-T. Tan).
Jenq-Yu Ko and Ming-Lang Kuo contributed equally to this work.
Received December 11, 2007; revised April 25, 2008; accepted April 29, 2008.