Ets1 transcription factor mediates gastrin-releasing peptide-induced IL-8 regulation in neuroblastoma cells.
Angiogenesis plays a critical role in tumor progression in various cancers, including neuroblastoma. We have previously shown that gastrin-releasing peptide (GRP) stimulates neuroblastoma growth and that its cell surface receptors, gastrin-releasing peptide receptors (GRP-R), are overexpressed in advanced-stage human neuroblastomas; however, the effects of GRP on angiogenesis are not clearly elucidated. Interleukin (IL) 8, a proinflammatory chemokine, plays an important role during tumor angiogenesis. Ets transcription factors, such as oncoproteins, cause tumor development and are also known to induce IL-8 expression. In the present study, we found an increased expression of Ets1 in more undifferentiated human neuroblastomas. Stable transfection of SK-N-SH human neuroblastoma cells with Ets1 plasmid resulted in increased IL-8 luciferase activity and IL-8 secretion into cell culture media. Conversely, silencing of Ets1 resulted in a significant decrease in IL-8 secretion in SK-N-SH cells. Moreover, exogenous GRP treatment increased Ets1 (T38) phosphorylation and Ets1 nuclear accumulation, and enhanced Ets1 binding to its DNA consensus sequence, resulting in the stimulation of IL-8 mRNA expression and protein secretion. Our findings demonstrate that GRP upregulates proangiogenic IL-8 expression in an Ets1-dependent manner, suggesting a critical role of this process during GRP-induced neuroblastoma angiogenesis and metastasis.
Qiao
Jingbo
J
Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77555-0353, USA.
Kang
Jung-Hee
JH
Cree
Jeremy
J
Evers
B Mark
BM
Chung
Dai H
DH
D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D019886:Gastrin-Releasing Peptide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D050784:Proto-Oncogene Protein c-ets-1 / Q000032:analysis / Q000502:physiology*; D015533:Transcriptional Activation
C494041:ETS1 protein, human; D016209:Interleukin-8; D050784:Proto-Oncogene Protein c-ets-1; D019886:Gastrin-Releasing Peptide; D004247:DNA