2021 Fiscal Year Research-status Report
The role of activin combined with different gene mutations in colorectal cancer EMT
| Project/Area Number |
21K15502
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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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| Keywords | activin / driver gene mutation / colorectal cancer / EMT |
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| Outline of Annual Research Achievements |
In this project, we investigated the role and mechanism of activin in malignant progression of colorectal cancer. In FY2021, I treated the mouse intestine tumor derived organoids with different combination of driver gene mutations with activn. We found that organoids with the Kras mutation were able to survive after activin stimulation, whereas activin induces growth suppression in organoids without the Kras mutation, indicating that the Kras activation mutation protects cells from activin-induced growth suppression. Importantly, we found that activin induces protrusion of organoids and promotes lung metastasis in p53 mutation-dependent manner. All of these results indicated that the background genetic alterations play an important role in activin-induced metastasis.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
As TGF-β induces apoptosis in normal cells and promotes EMT in malignant cancer cells; activin shares the same downstream genes with TGF-β; accumulation of key driver gene mutations causes gradual acquisition of malignant phenotypes. Accordingly, we make a hypothesis that simple or certain combined genetic alterations in driver genes may change the cell characteristics in response to activin. In our results, we found two driver mutations control the response to activin that Kras mutation inhibits activin-induced cell proliferation arrest; p53 mutation interacts with activin to induce metastasis. These results confirmed that driver gene mutations play an important role in activin-induced malignant progression.
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| Strategy for Future Research Activity |
Our results suggest that responses to activin-induced EMT process is closely related to the mutation status of p53. Based on this, we will conduct the following studies: 1. Confirm what kind of p53 mutations is important for activin-induced EMT. Different status of p53 mutations will be introduced in the organoids by Crispr system to examine metastasis after activin treatment. 2. what is the mechanism by which activin interacts with mutated p53 to regulate metastasis? RNA sequence will be performed to investigate the possible mechanism.
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