The anti-osteosarcoma strategy targeting functions of RUNX transcription factors

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02972
• 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)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 骨肉腫 / p53 / Runx3 / c-Myc

Outline of Final Research Achievements

Osteosarcoma (OS) in human patients is characterized by genetic alteration of TP53. Osteoprogenitor-specific p53-deleted mice (OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown.
In this study, we detected prominent RUNX3/Runx3 expression in human and mouse p53-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the Myc promoter, in a manner dependent on p53 deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of p53-deficient OS cells and effectively suppressed OS development in OS mice. These results show that p53 deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression via mR1.

Free Research Field

分子腫瘍学

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「mR1」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した。今後はこれらの成果をもとに、① 核酸標的薬をデザイン・開発してゲノム上でmR1そのものをブロックすること、あるいは、② mR1上のRunx3と他の因子の機能を阻害する化合物を同定・開発することで、抗骨肉腫創薬に役立てていきたい。