| Project/Area Number |
17H04064
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Nagoya University |
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Principal Investigator |
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| 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)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
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| 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 / 腫瘍 / CTGF / オミクス解析 / 発がん / 多層オミクス解析 |
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| 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.
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| 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。
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