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Carcinogenesis Advance Access originally published online on February 28, 2008
Carcinogenesis 2008 29(8):1483-1492; doi:10.1093/carcin/bgn045
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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Bone-derived SDF-1 stimulates IL-6 release via CXCR4, ERK and NF-{kappa}B pathways and promotes osteoclastogenesis in human oral cancer cells

Chih-Hsin Tang1,*, Jing-Yuan Chuang2, Yi-Chin Fong3,4,5, Ming-Chei Maa6, Tzong-Der Way7 and Chien-Hui Hung8

1 Department of Pharmacology
2 Department of Medical Laboratory Science and Biotechnology
3 Department of Orthopaedics
4 School of Chinese Medicine
5 Graduate Institute of Chinese Medical Science
6 Institute of Medical Science
7 Department of Biological Science and Technology
8 Department of Microbiology, China Medical University, Taichung 404, Taiwan

* To whom correspondence should be addressed. Tel: +886 4 22053366 2228; Fax: +886 4 22053764; Email: chtang{at}mail.cmu.edu.tw

Oral squamous cell carcinoma (SCC) has a striking tendency to invade to bone. The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively secreted by osteoblasts and plays a key role in homing of hematopoietic cells to the bone marrow. Interleukin (IL)-6 plays an important role in osteoclastogenesis. Herein, we found that SDF-1{alpha} increased the secretion of IL-6 in cultured human SCC cells, as shown by reverse transcriptase–polymerase chain reaction and enzyme-linked immunosorbent assay. SDF-1{alpha} also increased the surface expression of chemokine receptor 4 (CXCR4) in SCC cells. CXCR4-neutralizing antibody, CXCR4-specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited SDF-1{alpha}-induced increase IL-6 production. The transcriptional regulation of IL-6 by SDF-1{alpha} was mediated by phosphorylation of extracellular signal-regulated kinases (ERKs) and activation of the nuclear factor-kappa B (NF-{kappa}B) components p65 and p50. The binding of p65 and p50 to the NF-{kappa}B element on the IL-6 promoter was enhanced by SDF-1{alpha}. In addition, IL-6 antibody antagonized the SCC-conditioned medium-increased osteoclastogenesis. These results suggested that SDF-1{alpha} from osteoblasts could induce release of IL-6 in human SCC cells via activation of CXCR4, ERK and NF-{kappa}B pathway and thereby promote osteoclastogenesis.

Abbreviations: AP-1, activator protein-1; CXCR4, chemokine receptor 4; ERK, extracellular signal-regulated kinase; IL, interleukin; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MMP-9, matrix metalloproteinase; mRNA, messenger RNA; NF-{kappa}B, nuclear factor-kappa B; ODN, oligonucleotide; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PDTC, pyrrolidine dithiocarbamate; RANKL, receptor activator of nuclear factor-kappa B ligand; SCC, squamous cell carcinoma; SDF, stromal cell-derived factor; siCXCR4, small interfering RNA against CXCR4; siRNA, small interfering RNA; TRAP, artrate-resistant acid phosphatase

Received November 9, 2007; revised January 21, 2008; accepted February 2, 2008.


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