Hepatocyte growth factor/scatter factor differentially regulates expression of proangiogenic factors through Egr-1 in head and neck squamous cell carcinoma

Autor: Tin-Lap Lee, Joshua G. Cohen, Lorena Bagain, Xin Ping Yang, Carter Van Waes, Brian F Worden, Zhong Chen, Ning T. Yeh
Rok vydání: 2005
Předmět:
Vascular Endothelial Growth Factor A
Cancer Research
Platelet-derived growth factor
Angiogenesis
MAP Kinase Kinase 2
Molecular Sequence Data
MAP Kinase Kinase 1
Biology
Transfection
Immediate-Early Proteins
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Cell Line
Tumor
medicine
Humans
Angiogenic Proteins
RNA
Small Interfering
Transcription factor
Protein Kinase C
Early Growth Response Protein 1
Platelet-Derived Growth Factor
Base Sequence
Hepatocyte Growth Factor
Interleukin-8
Oligonucleotides
Antisense
medicine.disease
Head and neck squamous-cell carcinoma
Molecular biology
body regions
Vascular endothelial growth factor
DNA-Binding Proteins
Gene Expression Regulation
Neoplastic
Vascular endothelial growth factor A
Oncology
chemistry
Head and Neck Neoplasms
biology.protein
Cancer research
Carcinoma
Squamous Cell
Hepatocyte growth factor
Microdissection
hormones
hormone substitutes
and hormone antagonists
Platelet-derived growth factor receptor
medicine.drug
Transcription Factors
Zdroj: Cancer research. 65(16)
ISSN: 0008-5472
Popis: Hepatocyte growth factor/scatter factor (HGF) and the angiogenesis factors platelet-derived growth factors (PDGF), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) are found in elevated concentrations in serum or tumor tissue of patients with head and neck squamous cell carcinomas (HNSCC), suggesting these factors may be coregulated. A cDNA microarray analysis for HGF-inducible genes revealed that HGF also modulates PDGFA expression, a gene recently shown to be inducible by the transcription factor, early growth response-1 (Egr-1). In the present study, we investigated the potential role of HGF-induced Egr-1 in expression of PDGF, VEGF, and IL-8. HGF induced expression of all three factors and Egr-1 expression and DNA-binding activity. The analysis of promoter sequences showed putative Egr-1 binding sites in the PDGFA or VEGF but not in the IL-8 promoter, and HGF-induced Egr-1–binding activity was confirmed by chromatin immunoprecipitation (ChIP) assay. The maximal basal and HGF-induced promoter activity for the PDGFA gene existed within −630 bp of the promoter region, and overexpression of Egr-1 significantly increased such activity. Consistent with this, expression of PDGFA and VEGF but not IL-8 showed corresponding differences with Egr-1 expression in HNSCC tumor specimens and were strongly suppressed by transfection of Egr-1–antisense or small interference RNA (siRNA) oligonucleotides. HGF-induced expression of Egr-1, PDGFA, and VEGF was suppressed by pharmacologic and siRNA inhibitors of mitogen-activated protein kinase kinase 1/2 (MEK1/2) and protein kinase C (PKC) pathways. We conclude that the HGF-induced activation of transcription factor Egr-1 by MEK1/2- and PKC-dependent mechanisms differentially contributes to expression of PDGF and VEGF, which are important angiogenesis factors and targets for HNSCC therapy.
Databáze: OpenAIRE
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