2021 Fiscal Year Final Research Report
Establishment of system for genomic mutation analysis using tissue stem cell in intestinal tumor
| Project/Area Number |
19H04268
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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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| Review Section |
Basic Section 63020:Radiation influence-related
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| Research Institution | Osaka University |
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Principal Investigator |
Ishikawa-Fujiwara Tomoko (石川智子) 大阪大学, 放射線科学基盤機構附属ラジオアイソトープ総合センター, 特任研究員(常勤) (70402922)
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| Co-Investigator(Kenkyū-buntansha) |
辻村 亨 兵庫医科大学, 医学部, 教授 (20227408)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | 損傷乗り越えDNA合成 / 遺伝的不安定性 / 発がん / ミスマッチ修復 / Structure Variant (SV) / 二重鎖切断(DSB) / 点突然変異 |
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| Outline of Final Research Achievements |
We have been trying to establish a spontaneous tumorigenesis model system that can analyze the correlation between genome mutations and tumorigenesis in detail. We have already found intestinal tumor prone rev3 deficient medaka mutant. In this study we found expression of several tumor-related genes were up- or down-regulated in tumor cells derived from abdominal cavity of the rev3 mutant using RNA-Seq. We generated double mutants with rev3 for other TLS polymerases (polh, polk, poli) which suppress induction of genome structure variants (SVs), for msh2 which is involved in nucleotide level mutations, and for atm which is involved in regulation of double strand break repair and subsequent chromosomal level rearrangements. In all case, the life span was shortened additionally in double mutant compared to each single mutant. These results suggest that induction of point mutations and SVs have additive effects on tumorigenesis, and that DSB repair has suppressive effect on SV induction.
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| Free Research Field |
分子放射線生物学
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| Academic Significance and Societal Importance of the Research Achievements |
がんは我が国でも死因の上位に占める疾患で、突然変異誘発が「発がん」の有力要因である事は明らかである。本研究では大腸がんを自然発症するメダカにおいて、がん細胞では哺乳類同様がん関連遺伝子の発現の上昇、低下が観察され、他の、突然変異を誘発する遺伝子との二重変異体では表現型が亢進することが示された。このように遺伝子変異と発がん過程進行がリアルタイムにモニタリングできる実験モデル動物系の開発により発がんのイニシエーションからプロモーションの変遷における遺伝子変異の役割解明か可能となると考えられる。今後、本系の完成により当該分野のみならず、広く生物・医学分野で極めて大きな役割を果たすと考えられる。
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