Exploring the transcriptional repressors of VEGFA by in vitro/in vivo high throughput screening

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15236
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Muramatsu Tomoki 東京医科歯科大学, 難治疾患研究所, 助教 (90732553)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: VEGFA / 血管新生 / がん転移 / ニワトリ胚

Outline of Final Research Achievements

Angiogenesis in cancer contributes to transferring cancer cells to the other organs via new blood vessels. In the present study, we used chemical compound libraries containing 400 compounds for identification of novel transcriptional inhibitors of vascular endothelial growth factor A (VEGFA), a major regulator of angiogenesis. We first evaluated the expression of VEGFA using qRT-PCR after treatment with each compound and extracted some candidate compounds as VEGFA transcriptional inhibitors. Interestingly, almost all of these compounds can inhibit the same signaling pathway. We next confirmed that these compounds could inhibit the tube formation of endothelial cells and angiogenesis in chicken embryo. Moreover, we performed gene expression array with several samples treated with each candidate compound for identification of target genes. Our findings suggest that these compounds might have the potential of anti-angiogenic therapy for cancer.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

がん治療における血管新生阻害治療は、既に臨床応用されており、着実に成果を上げているが、薬剤耐性の獲得、副作用、患者の層別化など多くの課題が残っている。上記課題を克服するためには、血管新生阻害剤の種類を増やすこと、詳細な血管新生機構を理解することが重要である。本研究では、血管新生に重要な遺伝子であるVEGFAの転写発現を抑制する新規血管新生阻害剤の同定を行った。本研究の成果は、新規VEGFA転写抑制化合物を見出し、血管新生阻害効果を明らかにしたことである。今後、化合物処理による分子メカニズムを明らかにすることで、血管新生における新規知見の発見、最終的には治療薬開発に貢献できると考えられる。