Integrated understanding of molecular mechanisms of osteosarcoma development focusing on Myc super-enhancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H03113
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: Nagasaki University
• Principal Investigator: Ito Kosei 長崎大学, 医歯薬学総合研究科(歯学系), 教授 (00332726)
• Co-Investigator(Kenkyū-buntansha): 神崎 秀嗣 秀明大学, 看護学部, 教授 (60807345)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: TGFβ / Runx3 / Myc / スーパーエンハンサー / C/ebpα

Outline of Final Research Achievements

Osx-Cre;p53f/f mice (herein; OS mice) have been widely utilized to study the mechanisms of osteosarcomagenesis. Using this line, we recently reported that Runx3 aberrantly upregulates c-Myc in the absence of p53, providing a molecular basis for osteosarcoma development. However, the environmental factors contributing to the Myc upregulation by Runx3 remain unknown. In this study, we found that TGFβ induces Myc upregulation in a Runx3-dependent manner through a Myc super-enhancer (MycSE) in p53-deficient cells. To further explore the significance of this finding in vivo, we generated the following genetically modified mouse lines; 1. a mouse line lacking MycSE (MycSEΔ), 2. a mouse line lacking the Runx binding sequence within MycSE (MycSERx m/m), and 3. a mouse line lacking the TGFβ type 2 receptor (Tgfbr2 flox).　Each of these lines was crossed with OS mice. The crossed lines exhibited delayed osteosarcoma development and extended lifespan compared to OS mice.

Free Research Field

分子腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究において、p53非存在下でRunx3によるc-Mycの発現誘導に必要なゲノム上のエレメントが明らかになり、TGFβ-Runx3-Mycの機軸が革新的な抗骨肉腫創薬ターゲットになりうることを、マウス生体レベルで確認できた。今後はこれらの成果をもとに、この機構のなかで中心的な役割をもつRunx3の特異的阻害剤、あるいは、Runx3と他の因子の相互作用を阻害する化合物を同定・開発することで、抗骨肉腫創薬につなげていきたい。