Targeting orphan nuclear receptor TR3/Nur77 for tumor angiogenesis

 描述(由申请人提供)：血管生成对于实体肿瘤的生长至关重要，超过最小尺寸。我们已经证明孤儿核受体TR3(小鼠同源NUR77)转录因子在肿瘤血管生成中起关键作用。在Nur77基因敲除小鼠中，血管内皮生长因子-A、组胺和5-羟色胺诱导的肿瘤生长和血管生成几乎完全被抑制。然而，Nur77基因缺失的小鼠是存活的、有生育能力的，发育出表面上正常的成年血管系统，在正常的皮肤伤口愈合中没有缺陷。综上所述，这些发现表明TR3/Nur77是病理性血管生成所必需的，而不是发育或生理性血管生成所必需的，这使其成为抗血管生成治疗的潜在有用靶点。在体内的Matrigel血管生成实验中，我们还发现表达TR3/Nur77siRNA的逆转录病毒几乎完全抑制了VEGF-A诱导的血管生成。在目前的方案中，我们将确定靶向TR3/Nur77的生物分子来抑制肿瘤的生长和转移。在特定的目标下，我们将确定靶向TR3/Nur77是否能够抑制肿瘤的生长和转移。这项研究将确定siRNA和多肽，这些可能在癌症的抗血管生成治疗中具有潜力，为转录因子可以 要有针对性。这个应用程序具有翻译潜力。

 DESCRIPTION (provided by applicant): Angiogenesis is critical for solid tumor growth beyond minimal size. We have demonstrated that orphan nuclear receptor TR3 (mouse homolog Nur77) transcription factor plays critical roles in tumor angiogenesis. Tumor growth and angiogenesis induced by VEGF-A, histamine and serotonin are almost completely inhibited in Nur77 knockout mice. However, Nur77 null mice are viable, fertile, develop an apparently normal adult vasculature and have no defect in normal skin wound healing. Together these findings suggest that TR3/Nur77 is required for pathological angiogenesis, but not for developmental or physiological angiogenesis, and render it a potentially useful target for anti-angiogenic therapy. We also found that retroviruse expressing TR3/Nur77 siRNA almost completely inhibits the angiogenesis induced by VEGF-A in a Matrigel angiogenesis assay in vivo. In the present proposal, we will identify biomolecules that target TR3/Nur77 to inhibit tumor growth and metastasis. In specific Aim, we will determine whether tumor growth and metastasis can be inhibited by targeting TR3/Nur77. This research will identify siRNA and peptides that could have potential in anti-angiogenic therapy for cancer, providing evidence that a transcription factor can be targetable. This application has translation potential.