| Project/Area Number |
17K07162
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Kanazawa University |
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Principal Investigator |
Nakayama Mizuho 金沢大学, がん進展制御研究所, 助教 (20398225)
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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 |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 大腸がん / 悪性化 / p53 LOH / 転移 / p53 / Loss of heterogeneity / マウスモデル |
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| Outline of Final Research Achievements |
The accumulation of driver gene mutations causes colorectal cancer (CRC). However, it still unknown that which gene is responsible for metastasis. Previously, we generated CRC mouse model which carries four driver gene mutations (Apc, Kras, Tgfbr2, p53; AKTP) and established the organoids from mouse tumor.
This project focused p53 which is the most frequently mutated gene in pan-cancer cohort. We found that LOH of wild type-p53 with mutation cells (AKTPLOH/M), that p53 status is frequently seen in human malignant tumor, are enriched in metastasis legions when AKTP+/M organoids are injected in mouse spleen. Moreover, p53 LOH is required for the dormant cell survival and clonal expansion abilities. RNA seq. analyses revealed that inflammatory and growth factor/MAPK pathways are activated in AKTPLOH/M cells, while the stem cell signature is upregulated in both AKTPNull and AKTPLOH/M cells, indicating p53 LOH promotes mutant p53 driven metastasis through a distinct pathway activation.
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| Academic Significance and Societal Importance of the Research Achievements |
大腸がんの転移に関わる原因遺伝子はわかっていない。本研究は多くのがんで変異が入っているp53に着目し、大腸がん転移前後のp53遺伝子とそれに伴う腫瘍細胞の悪性形質を調べた。p53に変異が入っただけでは悪性度は低いが、これに野生型p53欠損（LOH）が組み合わさることで、高い転移能力を獲得していることが分かった。ヒトのがんで見つかるp53の多くが変異＋LOHの組み合わせであることから、このようなp53は転移における責任遺伝子のひとつであることが示唆された。この研究によりp53変異によるがん悪性化の詳細なメカニズムが明らかとなり、また創薬の分野においてもp53はターゲットとして広がりが期待される。
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