A homeobox gene related to Drosophila Distal-less promotes ovarian tumorigenicity by inducing expression of vascular endothelial growth factor and fibroblast growth factor-2 Free

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Homeobox genes encode transcription factors that control cell differentiation and play essential roles in developmental patterning. Increasing evidence indicates that many homeobox genes are aberrantly expressed in cancers. DLX4 belongs to the DLX family of mammalian homeobox genes that are related to the Drosophila gene Distal-less, and maps to the 17q21.3-q22 region that is amplified in some ovarian cancers. Because amplification of this region correlates with poor prognosis, we investigated whether DLX4 overexpression contributes to aggressive behavior of this disease. DLX4 was found to be absent from normal ovary and benign cystadenomas, whereas its expression in malignant ovarian tumors strongly associated with high tumor grade, advanced disease stage and ascites formation. Overexpression of DLX4 in ovarian cancer cells promoted growth in low serum and colony formation. Imaging of mice bearing i.p. tumors revealed that DLX4 overexpression substantially increased tumor burden, dissemination and ascites formation. Furthermore, tumors that overexpressed DLX4 were more vascularized than vector-control tumors. Conditioned medium of DLX4-overexpressing tumor cells stimulated endothelial cell growth. These observations were associated with the ability of DLX4 to induce expression of vascular endothelial growth factor (VEGF), and also intracellular and secreted isoforms of fibroblast growth factor-2 (FGF-2). Moreover, increased levels of these FGF-2 isoforms induced VEGF expression in tumor cells. This study reveals a novel role for a homeobox gene in ovarian tumorigenicity by its induction of a pro-angiogenic, growth-stimulatory molecular program.