The homeoprotein DLX4 controls inducible nitric oxide synthase-mediated angiogenesis in ovarian cancer

Molecular Cancer

Research

Bon Trinh¹  Dhwani Haria¹  Honami Naora¹  Song Yi Ko¹  Nicolas Barengo¹ 

[1] Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;

关键词: Angiogenesis;    Ovarian cancer;    Nitric oxide synthase;    Homeobox gene;   

DOI  :  10.1186/s12943-015-0368-3

 received in 2015-03-10, accepted in 2015-04-17,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundHomeobox genes encode transcription factors that control patterning of virtually all organ systems including the vasculature. Tumor angiogenesis is stimulated by several homeobox genes that are overexpressed in tumor cells, but the mechanisms of these genes are poorly understood. In this study, we investigated the mechanisms by which DLX4, a homeobox gene that is associated with increased tumor microvessel density, stimulates ovarian tumor angiogenesis.MethodsExpression of DLX4 and nitric oxide synthases was analyzed in publicly available transcriptional profiles of ovarian cancer clinical specimens. Levels of inducible nitric oxide synthase (iNOS) were evaluated by quantitative RT-PCR, flow cytometry and nitric oxide assays using ovarian cancer cell lines in which DLX4 was overexpressed or knocked down. Signal Transducer and Activator of Transcription 1 (STAT1) expression and activity were evaluated by luciferase reporter assays, immunofluorescence staining, Western blot and immunoprecipitation. Endothelial cell growth and tumor angiogenesis were evaluated in in vitro assays and xenograft models.ResultsWe identified that DLX4 induces expression of iNOS, an enzyme that stimulates angiogenesis by generating nitric oxide. Analysis of datasets of two independent patient cohorts revealed that high DLX4 expression in ovarian cancer is strongly associated with elevated expression of iNOS but not of other nitric oxide synthases. Studies using STAT1-expressing and STAT1-deficient cells revealed that DLX4 interacts with STAT1 and induces iNOS expression in part by stimulating STAT1 activity. Expression of DLX4 in ovarian cancer cells stimulated endothelial cell growth in vitro and increased microvessel density in xenograft models, and these stimulatory effects of DLX4 were abrogated when its induction of iNOS was inhibited.ConclusionThese findings indicate that DLX4 promotes ovarian tumor angiogenesis in part by stimulating iNOS expression.

【 授权许可】

Unknown   
© Trinh et al.; licensee BioMed Central. 2015. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.