| Project/Area Number |
16H02468
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Aichi Cancer Center Research Institute (2018-2020)
Nagoya University (2016-2017) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
宮野 悟 東京大学, 医科学研究所, 教授 (50128104)
山口 知也 熊本大学, 大学院先導機構, 准教授 (70452191)
松下 博和 愛知県がんセンター(研究所), 腫瘍免疫制御TR分野, 分野長 (80597782)
梶野 泰祐 愛知県がんセンター(研究所), 分子診断TR分野, 主任研究員 (50723673)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥45,500,000 (Direct Cost: ¥35,000,000、Indirect Cost: ¥10,500,000)
Fiscal Year 2019: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2018: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2017: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000)
Fiscal Year 2016: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
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| Keywords | がん / がん遺伝子 / ノックアウトマウス / シグナル伝達 / ROR1 / TTF-1/NKX2-1 / HIF-1 / 癌 / 遺伝子発現制御 / システム生物学 |
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| Outline of Final Research Achievements |
We previously discovered that TTF-1 acts as a lineage-survival oncogene in lung adenocarcinoma and regulates ROR1, which functions as a scaffold protein for CAV1 and CAVIN1 for caveolae formation. In this study, we have found that ROR1 binds to CAVIN3, playing an important role in caveolae-dependent endocytosis. Ror1 conditional knockout (KO) mice were generated and crossed with SP-C-driven mutant EGFR transgenic mice. It was shown for the first time that Ror1 KO significantly inhibited lung adenocarcinoma development in vivo and prolonged survival of the mouse lung cancer model, strongly supporting a notion that ROR1 is a prime molecular target. In addition, we found that HIF-1α expression is maintained by the presence of ROR1 in lung adenocarcinoma cells. As for TTF-1, miR-532 was found to be regulated by TTF-1 and directly targets KRAS and MKL2. TTF-1 also conferred tolerance for DNA replication stress through its binding to DDB1 and consequential stabilization of CHK1.
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| Academic Significance and Societal Importance of the Research Achievements |
肺腺がんのリネジ生存がん遺伝子として同定したTTF-1/NKX-2-1が、生存シグナルを担う分子メカニズムについて多角的な情報を得ることができた。本研究課題の遂行は、受容体型チロシンキナーゼの中で分子機能に関する知見の集積が大きく遅れていたROR1に関する多くの新知見の獲得につながり、未だ難治がんの代表例の一つの肺腺がんの革新的な分子標的薬の開発の基盤となる情報が得られた。
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