| Project/Area Number |
17K08678
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Pathological medical chemistry
|
|---|
| Research Institution | Osaka Medical College |
|---|
Principal Investigator |
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
朝日 通雄 大阪医科大学, 医学部, 教授 (10397614)
|
|---|
| Project Period (FY) |
2017-04-01 – 2020-03-31
|
| Project Status |
Completed (Fiscal Year 2019)
|
| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
|
|---|
| Keywords | O-GlcNAc修飾 / 炎症性サイトカイン / 癌 / NF-κB / p38 / 糖鎖 |
|---|
| Outline of Final Research Achievements |
Elevated O-GlcNAcylation is a dynamic post-translational modification to play a crucial role in various caner phenotypes and caner progression. This suggests that it may be a potential new therapeutic target for cancer therapy. However, the role of O-GlcNAcylation in tumor progression, especially, in tumor microenvironment (TME) is not fully elucidated. Here, we examined the function of elevated TME O-GlcNAcylation using a subcutaneous mice model of B16 melanoma cells in Ogt-transgenic (Ogt-Tg) mice. In this model system, elevated O-GlcNAcylation decreased infiltration of M1-like (F4/80+iNOS+) cells into B16 tumors and production of pro-inflammatory cytokine in Ogt-Tg mice compared with wild-type mice. In the tumors excised from Ogt-Tg mice, NF-κB and p38 activity was significantly reduced, while ERK signaling was increased. These data suggest that O-GlcNAcylation in the TME may reduce production of pro-inflammatory cytokines and promote tumor growth through suppression of p38 MAPK.
|
| Academic Significance and Societal Importance of the Research Achievements |
O-GlcNAc修飾は、癌の治療標的として期待されてきたが、癌微小環境におけるO-GlcNAc修飾の機能は知見に乏しく、糖尿病患者では癌が進行しやすいと言われてO-GlcNAc修飾の関与も示唆されてきたが、その分子機序の全容は分かっていなかった。本研究により、癌微小環境におけるO-GlcNAc修飾の亢進が、腫瘍攻撃性の免疫細胞の機能を低下させることにより癌の増殖を促進していることが示唆され、癌の進展、および、糖尿病における癌の進展促進に働くその分子機序の一端を見出すことができた。
|
