Carcinogenesis Advance Access originally published online on October 9, 2008
Carcinogenesis 2009 30(2):205-213; 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 100, Taiwan
2 Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine and Angiogenesis Research Center, National Taiwan University, No.1, Sec.1, Jen-Ai Road, Taipei 100, Taiwan
3 Department of Dermatology, Mackay Memorial Hospital, Taipei 100, Taiwan
4 Department of Otolaryngology
5 Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
* To whom correspondence should be addressed. Tel: +886 2 2312 3456 8607; Fax: +886 2 2341 0217; Email: kuominliang{at}ntu.edu.tw
Correspondence may also be addressed to Shiou-Hwa Jee. Tel: +886 2 2356 2141; Fax: +886 2 2393 4177; Email: shiouhwa{at}ntu.edu.tw
Stromal cell-derived factor 1
(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 with 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 upregulated several angiogenesis-associated genes such as interferon-alpha-inducible protein 27, interleukin (IL)-6, bone morphogenetic protein (BMP)-6, SOCS2 and cyclooxygenase 2 (COX)-2 in human BCC cells. Among them, IL-6 was the earliest and highest upregulated gene whose induction was observed within 6 h of the commencement of SDF-1–CXCR4 interaction. The mechanisms behind the SDF-1-induced time and dose-dependent upregulation of messenger RNA 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 and activation of the nuclear factor-
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).
Abbreviations: AP, activator protein; BCC, basal cell carcinoma; bFGF, basic fibroblast growth factor; BMP, bone morphogenetic protein; CM, conditioned medium; COX, cyclooxygenase; ERK1/2, extracellular signal-related kinase 1/2; HUVEC, human umbilical vein endothelial cell; IFI27, interferon-alpha-inducible protein 27; IL, interleukin; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; MVD, microvessel density; NF-B, nuclear factor-B; RT, reverse transcription; SCC, squamous cell carcinoma; SDF-1, stromal cell-derived factor 1; VEGF, vascular endothelial growth factor
These authors contributed equally to this work. Received May 17, 2008; revised September 22, 2008; accepted September 28, 2008.
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