Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2-NF-kappaB/interleukin-6 pathway.
Stromal cell-derived factor 1alpha (SDF-1alpha) (CXCL12) has been observed to enhance tumor angiogenesis. However, the comprehensive role of SDF-1alpha (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-1alpha induced angiogenic activity in human BCC cells, both in vitro and in vivo. SDF-1alpha 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-1alpha-CXCR4 interaction. The mechanisms behind the SDF-1alpha-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-1alpha was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the nuclear factor-kappaB complex. The identification of the angiogenic profiles induced through SDF-1alpha-CXCR4 interactions in human BCC cells may contribute further insights into the mechanisms involved in the angiogenic potential of SDF-1alpha (CXCL12).
Chu
Chia-Yu
CY
Department of Dermatology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Cha
Shih-Ting
ST
Lin
Wan-Chi
WC
Lu
Po-Hsuan
PH
Tan
Ching-Ting
CT
Chang
Cheng-Chi
CC
Lin
Ben-Ren
BR
Jee
Shiou-Hwa
SH
Kuo
Min-Liang
ML
D014408:Biomarkers, Tumor / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism; D012878:Skin Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D054377:Chemokine CXCL12; D015850:Interleukin-6; D016328:NF-kappa B; D019718:Receptors, CXCR4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3