| Project/Area Number |
19K23882
|
|---|
| Research Category |
Grant-in-Aid for Research Activity Start-up
|
| Allocation Type | Multi-year Fund |
|---|
| Review Section |
0901:Oncology and related fields
|
|---|
| Research Institution | Kanazawa University |
|---|
Principal Investigator |
WANG DONG 金沢大学, ナノ生命科学研究所, 特任助教 (20842983)
|
|---|
| Project Period (FY) |
2019-08-30 – 2021-03-31
|
| Project Status |
Completed (Fiscal Year 2020)
|
| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
|
|---|
| Keywords | activin / driver gene mutation / colorectal cancer / EMT / Activin / p53 mutation / organoids |
|---|
| Outline of Research at the Start |
Although TGFβ has been shown to induce EMT in malignant tumor, 30% colorectal cancer carry genetic alterations in TGFβ pathway. Since activin shares the same downstream molecules Smad2/3 as TGFβ, activin may also induce EMT. However, the role of activin in tumorigenesis especially in TGFβ receptor-mutated cancer has not been elucidated yet. In this study, it will be verified whether Activin is capable of inducing EMT. And the mechanism by which activin induces EMT and the regulatory relationship between activin and mutant genes will be elucidated.
|
| Outline of Final Research Achievements |
In order to know the role of activin in colorectal cancer EMT and which driver gene mutations contribute to activin's conversion from induction of apoptosis to induction of EMT, the organoids with different combination of driver gene mutations were simulated with activin and the cell survival and EMT were examined. Cell survival: by using activin simulation and blocking Kras-MEK signaling, we found that Kras mutation inhibits activin-induced apoptosis. Morphological changes: we found that activin induces EMT via interacting with p53 homozygous mutation. In vivo: activin pretreated organoids form more lung metastasis. For mechanism: by using RNA-seq, we found that under the regulation of activin and p53 homozygous mutation, some signaling pathways, such as Wnt, p38-MAPK, Stat3 signaling, were upregulated. According to these findings we will be able to test some inhibitors for inhibiting the morphological changes and the candidate inhibitors may be used for clinical trial.
|
| Academic Significance and Societal Importance of the Research Achievements |
In this project, we explored the role and mechanism of activin in colorectal cancer EMT. We found that activin induces EMT by interacting with Kras and p53 mutations, which expands our knowledge about EMT mechanism and contributes to the development of anti-cancer drugs.
|
