Stromal cell-derived factor-1α (SDF-1α/CXCL12)-enhanced angiogenesis of human basal cell carcinoma cells involves ERK1/2–NF-κB/interleukin-6 pathway.

Stromal cell-derived factor 1α (SDF-1α) (CXCL12) has been observed to enhance tumor angiogenesis. However, the comprehensive role of SDF-1α (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-1α induced angiogenic activity in human BCC cells, both in vitro and in vivo. SDF-1α 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-1α–CXCR4 interaction. The mechanisms behind the SDF-1α-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-1α was mediated by phosphorylation of extracellular signal-related kinase 1/2 and activation of the nuclear factor-κB complex. The identification of the angiogenic profiles induced through SDF-1α–CXCR4 interactions in human BCC cells may contribute further insights into the mechanisms involved in the angiogenic potential of SDF-1α (CXCL12). [ABSTRACT FROM PUBLISHER]