| Project/Area Number |
21K15502
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
WANG DONG 金沢大学, ナノ生命科学研究所, 特任助教 (20842983)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | activin / driver gene mutation / colorectal cancer / partial EMT / EMT |
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| Outline of Research at the Start |
TGF-β has been reported to induce EMT in malignant cancer, however, the mechanism of activin (which shares the same downstream genes with TGF-β) in malignant progression has not been fully understood. In this proposal, mouse intestinal tumor-derived organoids carrying multiple mutations will be treated with activin to examine whether EMT is induced. RNA sequencing, in vitro and in vivo studies will be performed to elucidate how genetic mutations are involved in activin-induced EMT. The results will expand our knowledge about EMT, which contributes to development of novel anti-cancer drugs.
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| Outline of Final Research Achievements |
This project focuses on identifying genetic mutations that determine the outcome of TGFβ signaling. KrasG12D mutation protected organoid cells from activin A (TGFβ superfamily cytokine)-induced growth suppression by inhibiting p21 and p27 expression. Furthermore, Trp53R270H gain-of-function (GOF) mutation together with loss of wild-type Trp53 by loss of heterozygosity (LOH) promoted activin A-induced partial EMT and increased metastatic incidence. RNA sequencing analysis indicated that expression of Hmga2 was significantly upregulated in organoids with Trp53 GOF/LOH alterations. Importantly, loss of HMGA2 blocked activin A-induced partial EMT and metastasis in Trp53 GOF/LOH organoids. These results indicate that TP53 GOF/LOH is a key genetic state that primes for TGFβ family-induced partial EMT and malignant progression of colorectal cancer. Activin signaling may be an effective therapeutic target for colorectal cancer harboring TP53 GOF mutations.
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| Academic Significance and Societal Importance of the Research Achievements |
In this project, we clarified the function and mechanism of activin in colon cancer. The findings indicate that activin signaling may be an effective therapeutic target for colorectal cancer harboring TP53 GOF mutations and expand our knowledge about EMT mechanism.
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