Oncogenicity of Ggct, gamma-glutamylcyclotransferase in osteosarcomagenesis

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K17018
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: Nagasaki University
• Principal Investigator: Otani Shohei 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (90823336)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 骨肉腫 / Ggct / p53 / Myc

Outline of Final Research Achievements

Ggct is an enzyme involved in γ-glutamyl cycle that is essential for GSH homeostasis and has been frequently reported for its oncogenicity. Actually, Ggct is upregulated in osteosarcoma. In human osteosarcoma, suppression of Ggct reduces proliferation, migration, and invasion of osteosarcoma cell. Therefore, in this study, we used osteoprogenitor-specific p53-deteted mice (Sp7Cre p53f/f; OS mice) that have been widely used as an animal model of human osteosarcoma and evaluated the oncogenic role of Ggct in osteosarcomagenesis. Deletion of Ggct prolonged life span of OS mice and reduced the incidence of osteosarcoma in OS mice. Furthermore, we identified the Myc-consensus sites in the Ggct promoter, deletion of which reduced expression of Ggct and tumorigenicity. These results demonstrate that Ggct is an attractive target for anti-cancer drug discovery.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

骨肉腫の好発年齢は10代で、治療法は未だに外科的切除が第一選択であるため、若くして ADL/QOL低下をもたらす。しかし、その発症分子機序はほとんど解明されていない。そこで本研究は、新規がん関連因子Ggctの骨肉腫発症における役割の解明を目的とした。その結果、骨肉腫発症において「がん遺伝子」MycがGgctを直接ターゲットにしており、Ggct欠損OSマウスは骨肉腫発症抑制および寿命の延長をもたらすことが明らかになった。本研究成果は、Ggctが骨肉腫治療に有効な創薬ターゲットとなる可能性を示唆しており、その機能解析を通して治療薬の開発へとつながる「橋渡しとなる知見」を提供するものである。