Carcinogenesis Advance Access published online on October 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn228
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Stromal-cell-derived factor-1
(SDF-1/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2-NF-
B/interleukin-6 pathway
1 Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
2 Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine and Angiogenesis Research Center, National Taiwan University, Taipei, Taiwan
3 Department of Dermatology, Mackay Memorial Hospital, Taipei, Taiwan
4 Department of Otolaryngology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
5 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
* To whom correspondence should be addressed: Min-Liang Kuo, PhD, Angiogenesis Research Center, Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University, No.1 Sec.1 Jen-Ai Rd., Taipei 100, Taiwan. Telephone: +886-2-23123456-8607; Fax: +886-2-2341-0217; E-mail: kuominliang{at}ntu.edu.tw
SDF-1
(CXCL12) has been observed to enhance tumor angiogenesis. However, the comprehensive role of SDF-1 (CXCL12)-CXCR4 interaction exerted during angiogenesis, has not been well understood. We have previously demonstrated that human basal cell carcinoma (BCC) tissues and a BCC cell line (BCC-1/KMC) had significant expression of CXCR4, whose level was higher in invasive than in the non-invasive BCC types. Here, we observed that human BCC tissues with high expression levels of CXCR4 had higher vascularity. Further, among the 71 BCCs diagnosed between the years 2004-2005, BCCs with high CXCR4 expression had concomitantly higher microvessel density, as compared to those with low CXCR4 expression (P < 0.001). We found that SDF-1 induced angiogenic activity in human BCC cells, both in vitro and in vivo. SDF-1 significantly up-regulated several angiogenesis-associated genes such as IFI27, IL-6, BMP-6, SOCS2, and COX-2 in human BCC cells. Among them, IL-6 was the earliest and highest up-regulated gene whose induction was observed within 6 hours of the commencement of SDF-1/CXCR4 interaction. The mechanisms behind the SDF-1-induced time and dose dependent up-regulation of mRNA expression and protein secretion of IL-6 were investigated. The transcriptional regulation of IL-6 by SDF-1 was mediated by phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2) and activation of the NF-
B complex. The identification of the angiogenic profiles induced through SDF-1/CXCR4 interactions in human BCC cells may contribute further insights into the mechanisms involved in the angiogenic potential of SDF-1 (CXCL12).
Key Words: angiogenesis • basal cell carcinoma • CXCR4 • interleukin-6 • SDF-1
6 S-H Jee and M-L Kuo contributed equally to this work.
Received May 17, 2008; revised September 22, 2008; accepted September 28, 2008.
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