Crosstalk between mechanism of metabolic abnormalies in congenital disorders and cancer cell metabolism

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K19504
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Tohoku University
• Principal Investigator: Aoki Yoko 東北大学, 医学系研究科, 教授 (80332500)
• Co-Investigator(Kenkyū-buntansha): 松原 洋一 国立研究開発法人国立成育医療研究センター, 所長室, 研究所長 (00209602) ; 新堀 哲也 東北大学, 医学系研究科, 准教授 (40436134) ; 井上 晋一 東北大学, 医学系研究科, 助教 (70622091)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Keywords: 先天異常症 / 代謝 / がん原遺伝子

Outline of Final Research Achievements

Costello syndrome is involved in RASopathies. We have generated Costello syndrome model mice and found that the mutant mice are resistant to high-fat diet-induced obesity. Histology of liver showed microvesicular hepatic steatosis, suggesting abnormal beta-oxidation.
In this study, we comprehensively analyzed glycolysis, gluconeogenesis, lipid metabolism, nucleic acid, and amino acid metabolism in addition to the revealed mitochondrial β-oxidation pathway in the liver. In mutant mice, the blood glucose level decreased and the expression of β-oxidation-related genes decreased. In addition, glycolysis and cholesterol synthesis are enhanced with increased glucagon levels, which is a hormone that regulates blood glucose level. Gluconeogenesis is decreased despite high glucagon. Surprisingly, however, changes in the expression of these genes involved in energy metabolism were not observed at all after fasting.

Free Research Field

先天性疾患

Academic Significance and Societal Importance of the Research Achievements

本研究は、HRASの活性化変異を発現するマウス個体における代謝性変化をみることで、がん細胞の代謝のin vivoモデルになるのではないかという発想から生まれた。HRAS活性化変異を有するマウスの網羅的な代謝パスウェイの解析を行うことで、コステロ症候群の患者さんでの成長障害や低血糖などのメカニズム解明に役だつ可能性がある。さらに研究を進めることでがん細胞における代謝や、がんの進展における代謝的変化などを俯瞰することが可能と考えられる。