Analyses based on iron dynamics and multiomics to overcome oxidative stress-induced carcinogenesis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H04064
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Nagoya University
• Principal Investigator: Toyokuni Shinya 名古屋大学, 医学系研究科, 教授 (90252460)
• Co-Investigator(Kenkyū-buntansha): 岡崎 泰昌 名古屋大学, 医学系研究科, 講師 (30403489) ; 赤塚 慎也 名古屋大学, 医学系研究科, 講師 (40437223) ; 山下 享子 公益財団法人がん研究会, がん研究所 病理部, 研究員 (50754975)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 鉄 / がん予防 / オミクス / 中皮腫 / 腎癌 / アスベスト / 瀉血 / 酸化ストレス

Outline of Final Research Achievements

This project was planned to establish a basis for novel cancer prevention by evaluating iron dynamics multidimensionally. We established the concept of ferroptosis, as catalytic Fe(II)-dependent regulated necrosis, based on our experience of iron-induced carcinogenesis. We used phlebotomy to remove excess iron in crocidolite-induced mesothelial carcinogenesis, which significantly prolonged survival and reduced tumor burden. We used knockout (KO) mice of 3 repair genes for 8-oxoguanine (Ogg1, Mutyh and Mth1) and found that Mutyh KO showed a tendency to increase iron-induced renal carcinogenesis whereas Mth1 KO significantly reduced crocidolite-induced malignant mesothelioma (MM) in females. MM induction by crocidolite was delayed in Dmt1 transgenic mice. We also found that carbonic anhydrase 9 (CA9) confers ferroptosis-resistance to MM cells in hypoxia. Thus, CA9 can be another target for cancer therapy. In conclusion, iron metabolism regulates not only carcinogenesis but tumor biology.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

新たな細胞死である2価鉄依存性制御性壊死フェロトーシスはがん細胞死のみならず、種々の病的・生理的状態にも関与していることが判明し、今後の研究の新たな切り口となった。瀉血による中皮腫予防効果がラットで確認され、種々の鉄代謝・酸化的DNA傷害修復遺伝子の鉄発がんへの作用が明らかとなった。炭酸脱水酵素9はフェロトーシス抵抗性を賦与しており、新たな治療標的となる。