Sp-1 and c-Myc Mediate Lysophosphatidic Acid–Induced Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Cells via a Hypoxia-Inducible Factor-1–Independent Mechanism
| Autor: | Yuanda Song, Regina A. Oyesanya, Abir Mukherjee, Jinhua Wu, Zendra Lee, Xianjun Fang |
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| Rok vydání: | 2009 |
| Předmět: |
Vascular Endothelial Growth Factor A
Cancer Research Small interfering RNA Sp1 Transcription Factor Biology Models Biological Article Proto-Oncogene Proteins c-myc chemistry.chemical_compound Cell Line Tumor Gene expression Lysophosphatidic acid Humans Phosphorylation RNA Small Interfering Promoter Regions Genetic Transcription factor Ovarian Neoplasms Sp1 transcription factor Neovascularization Pathologic Promoter Hypoxia-Inducible Factor 1 alpha Subunit Gene Expression Regulation Neoplastic Vascular endothelial growth factor Vascular endothelial growth factor A Oncology chemistry Cancer research Female lipids (amino acids peptides and proteins) Lysophospholipids biological phenomena cell phenomena and immunity |
| Zdroj: | Clinical Cancer Research. 15:492-501 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-08-1945 |
| Popis: | Purpose: Lysophosphatidic acid (LPA), which is present in ascites of ovarian cancer patients, stimulates expression of vascular endothelial growth factor (VEGF). VEGF is essential for the development and abdominal dissemination of ovarian cancer. We examined how LPA drives VEGF expression to gain a better understanding of tumor angiogenesis under normoxic conditions. Experimental Design: ELISA, Northern blotting, immunoblotting, quantitative PCR, and promoter reporter analysis in combination with small interfering RNA and pharmacologic inhibitors were used to examine LPA-induced VEGF expression and the underlying mechanisms. Results: LPA stimulated expression of multiple VEGF variants. A 123-bp fragment proximal to the transcriptional initiation site was identified to be functional promoter region responsible for the response to LPA. The fragment harbors consensus sites for several transcription factors including c-Myc and Sp-1 but not hypoxia-inducible factor-1. Blockade of Rho, ROCK, or c-Myc reduced LPA-dependent VEGF production and promoter activation, suggesting that the G12/13-Rho-ROCK-c-Myc cascade partially contributes to VEGF induction by LPA. More significantly, the multiple Sp-1 sites within the responsive region of the VEGF promoter were essential for LPA-mediated transcription. LPA induced Sp-1 phosphorylation and DNA-binding and transcriptional activities. The silencing of Sp-1 expression with small interfering RNA or inhibition of Sp-1 with pharmacologic inhibitors blocked VEGF production induced by LPA. Conclusions: LPA stimulates hypoxia-inducible factor-1-independent VEGF expression to promote tumor angiogenesis through activation of the c-Myc and Sp-1 transcription factors. |
| Databáze: | OpenAIRE |
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