2021 Fiscal Year Final Research Report
Understanding of the mechanism of gastric carcinogenesis by the development of the system that visualizes dynamics of the planar cell polarity within gastric epithelial organoids
| Project/Area Number |
19K05945
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 38060:Applied molecular and cellular biology-related
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | Wntシグナル伝達系 / 平面内細胞極性 / ヘリコバクター・ピロリ / CagA / PAR1b / Hippoシグナル伝達系 |
|---|
| Outline of Final Research Achievements |
I revealed that a bacterial oncoprotein CagA, which is injected into the gastric epithelial cells by Helicobacter pylori, has an activity to perturb the Wnt-Planar Cell Polarity (PCP) signaling pathway. The CagA-caused perturbation of Wnt-PCP signaling was due to the CagA-Protein X (a PCP core protein) complex formation via the N-terminal domain of the CagA protein. We identified BRCA1 as a novel substrate of PAR1b, a kinase responsible for apical-basal cell polarity. CagA inhibits the kinase activity of PAR1b therefore we found that CagA prevents the phosphorylation-dependent nuclear translocation of BRCA1, which is required for homologous recombination-driven repairing of DNA double strand breaks. The human YAP1 gene generates 8 isoforms through alternative splicing. We found that an alternative exon, the exon 6, plays a key role in the tumorigenic potential of the YAP protein in the subcutaneous of nude mice and then uncovered the molecular mechanism underlaying the phenomenon.
|
| Free Research Field |
分子腫瘍学、分子生物学、細胞生物学、細胞内シグナル伝達
|
| Academic Significance and Societal Importance of the Research Achievements |
頂端細胞極性に関わるPAR1bがゲノム安定性を制御することを示した。PAR1bはYAP1を介したHippoシグナルや平面内細胞極性の制御に重要である。本研究では、ピロリ菌のCagAによる「頂端/平面内細胞極性ーDNA傷害の修復ーHippoシグナル」の機能連関の撹乱を示した。病理学・疫学的な解析から、ピロリ菌／CagAは胃発がんに不可欠である。多段階発がん過程を経た胃のがん部にはピロリ菌は存在しないことから、CagAの注入が胃のがん化を開始する一方で、胃がん形成後にはCagAは不要であると考えられてきた（Hit and Run型の発がん）。本研究は世界に先駆けてこの機序を明らかにした。
|
