Early growth response-1 induces and enhances vascular endothelial growth factor-A expression in lung cancer cells.

Abstract

Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal-regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1-inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1alpha (HIF-1alpha)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1alpha and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1alpha expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression.

• Authors: Hiroaki Shimoyamada, Takuya Yazawa, Hanako Sato, Koji Okudela, Jun Ishii, Masashi Sakaeda, Korehito Kashiwagi, Takehisa Suzuki, Hideaki Mitsui, Tetsukan Woo, Michihiko Tajiri, Takahiro Ohmori, Takashi Ogura, Munetaka Masuda, Hisashi Oshiro, Hitoshi Kitamura
• Journal: The American journal of pathology (Am J Pathol) Vol. 177 Issue 1 Pg. 70-83 (Jul 2010) ISSN: 1525-2191 [Electronic] United States
• PMID: 20489156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• EGR1 protein, human
• Early Growth Response Protein 1
• Enzyme Inhibitors
• Hypoxia-Inducible Factor 1, alpha Subunit
• NAB2 protein, human
• Repressor Proteins
• Vascular Endothelial Growth Factor A
• Decitabine
• Extracellular Signal-Regulated MAP Kinases
• Azacitidine

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Animals
• Azacitidine (analogs & derivatives, pharmacology)
• Cell Line, Tumor (drug effects, metabolism)
• Decitabine
• Early Growth Response Protein 1 (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation, Neoplastic
• Genes, ras
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Lung Neoplasms (genetics, metabolism, pathology)
• Promoter Regions, Genetic
• RNA Interference
• Repressor Proteins (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)