Development of novel cancer therapy against ROS produced by unhealthy mitochondria in cancer cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08954
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Gifu University
• Principal Investigator: Futamura Manabu 岐阜大学, 大学院医学系研究科, 准教授 (10415515)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: Mieap / p53 / ミトコンドリア / がん代謝

Outline of Final Research Achievements

Mieap, a downstream gene of p53, plays an important role in mitochondrial quality control by eliminating/repairing unhealthy cancer mitochondria which produce less ATP and lots of reactive oxygen species (ROS). We previously reported the role of Mieap in colorectal and breast cancer. Mieap-NIX/BNIP3-Mieap-axis was impaired in these cancers. Overexpression of Mieap induced caspase-dependent apoptosis in these cells. Here we found Mieap was paired in both gastric and esophageal cancers. High rates of p53 mutation and/or methylation of BNIP3 promoter were frequent. Furthermore, to investigate the clinical significance of Mieap in breast cancer, we performed in-silico search using TCGA and METABRIC data base. Interestingly, we found loss of Mieap expression was significantly associated with clinical stage and survival by both cohorts. These results indicates that Mieap is a strong candidate of tumor suppressor in solid cancers such as breast and gastrointestinal cancers.

Free Research Field

分子腫瘍学・乳腺外科学

Academic Significance and Societal Importance of the Research Achievements

私たちの研究はがん抑制遺伝子p53の研究に始まり、がんのミトコンドリア、いわゆるがん代謝の研究へとシフトしています。遺伝子の異常はタンパク質の異常、ひいては細胞の機能異常につながっていきます。がんにおいて、遺伝子異常のみならず代謝の異常が、がんの性質や悪性度を決めているといえます。Mieapの機能はミトコンドリアの品質管理をすることで、細胞の悪性化を阻止していますが、この機能がなくなると悪性度が増し、患者さんの生存率にまで影響しているという知見が得られました。こうした重要な因子をコントロールすることが、これからのがん征圧、がん治療の道を開くことになるでしょう。