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Carcinogenesis Advance Access originally published online on October 4, 2007
Carcinogenesis 2008 29(1):35-43; doi:10.1093/carcin/bgm220
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Involvement of matrix metalloproteinase-9 in stromal cell-derived factor-1/CXCR4 pathway of lung cancer metastasis

Chih-Hsin Tang, Tzu-Wei Tan, Wen-Mei Fu1 and Rong-Sen Yang2,*

Department of Pharmacology, China Medical University, Taichung, 404 Taiwan
1 Department of Pharmacology
2 Department of Orthopaedics, College of Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 100 Taiwan

* To whom correspondence should be addressed. Tel: +886 2 23123456 ext. 3958; Fax: +886 2 23936577; Email: rsyang{at}ntuh.gov.tw Correspondence may also be addressed to Wen-Mei Fu. Tel: +886 2 23123456 ext. 8319; Fax: +886 2 23417930; Email: wenmei{at}ntu.edu.tw

Lung caner cells have a striking tendency to metastasize to bone. The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively secreted by osteoblasts and bone marrow stromal cells and plays a key role for homing of hematopoietic cells to the bone marrow. Reverse transcriptase–polymerase chain reaction and flow cytometry studies demonstrated SDF-1 receptor (CXCR4) messenger RNA (mRNA) and surface expression of CXCR4 in lung cancer cell lines, especially higher in those with high invasiveness (A549) as compared with lower level in H928 cells and H1299 cells. SDF-1, osteoblast-conditioned medium (OBCM) and stromal cell-conditioned medium all induced the invasiveness of lung cancer cells. Matrix metalloproteinase (MMP)-9 small interfering RNA inhibited the SDF-1{alpha}- or OBCM-induced MMP-9 expression and thereby significantly inhibited the SDF-1{alpha}- or OBCM-induced cell invasion. Furthermore, mitogen-activated protein kinase kinase inhibitor PD98059 suppressed SDF-1{alpha}-induced MMP-9 mRNA expression. Transient transfection with dominant-negative extracellular signal-regulated kinase (ERK) mutant also showed that the ERK-signaling pathway was involved in SDF-1{alpha}-induced MMP-9 expression. Moreover, nuclear factor-{kappa}B (NF-{kappa}B) decoy oligodeoxynucleotide suppressed the MMP-9 promoter activity enhanced by SDF-1{alpha}. Both mitogen-activated protein kinase kinase inhibitor and ERK mutant also antagonized SDF-1{alpha}-induced NF-{kappa}B-driven luciferase promoter activity. Taken together, our results indicated that bone marrow-derived-SDF-1{alpha} enhances the invasiveness of lung cancer cells by increasing MMP-9 expression through the CXCR4/ERK/NF-{kappa}B signal transduction pathway.

Abbreviations: ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; IKK, I{kappa}B kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mRNA, messenger RNA; NF-{kappa}B, nuclear factor-{kappa}B; NSCLC, non-small cell lung cancer; OBCM, osteoblast-conditioned medium; ODN, oligonucleotide; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; SDF-1, stromal cell-derived factor-1; SDS, sodium dodecyl sulfate; siRNA, small interfering RNA

Received June 9, 2007; revised August 23, 2007; accepted September 21, 2007.


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