| Project/Area Number |
16590278
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Human pathology
|
|---|
| Research Institution | Kobe University |
|---|
Principal Investigator |
KITAZAWA Sohei Kobe University, Graduate School of Medicine. Department of Pathology and Microbiology, Division of Pathology, Associate Professor, 大学院医学系研究科, 助教授 (90186239)
|
|---|
| Project Period (FY) |
2004 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2005: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
|
|---|
| Keywords | Non CpG-island / Methylation / Gene promoter / Bladder cancer / BAMBI / Gene transcription / Pancreatic cancer / TrkA / メチル化 / Desmoid tumor / 神経周囲浸潤 |
|---|
| Research Abstract |
Although global methylation at CpG islands leads to gene silencing, specific methylation at non-CpG islands would play a crucial epigenetic role in the versatility and plasticity of gene expression during cancer progression. We demonstrated the negative cis-acting AP-1-like sequence TGAGCGA in the 5'-untranslated region of the TrkA gene. Steady-state TrkA expression correlated positively with the accumulation of methylated CpG around the AP-1-like site. By EMSA, the AP-1-like site was bound mainly by c-Jun homodimers; the binding was blocked by Sss I-induced methylation. Consequently, activation of TrkA gene expression by methylation was caused by the direct interference of c-Jun binding to the negatively regulating AP-1-like site. Furthermore, methylated CpG around the AP-1-like site was accumulated with increased TrkA expression in cases of advanced pancreatic cancer with extensive perineural invasion.
A rare case of desmoid-type fibromatosis with metaplastic ossification in the chest wall is analyzed. Accumulation of beta-catenin associated with a somatic activating mutation in codon 41 was demonstrated. Bisulfite mapping using microdissected samples showed that BMP and activin membrane-bound inhibitor (BAMBI) expression was specifically downregulated at the ossifying focus due to hypermethylation of its gene promoter. Because both BMP and classical Wnt/beta-catenin/LEF1 signaling cooperatively and mutually induce differentiation of mesenchymal cells into osteoblastic cells and promote bone formation, the epigenetic event leading to the enhanced responsiveness to BMP signaling may play a crucial role in the formation of metaplastic bone.
We have presented our data at various international as well as domestic meetings, and published scientific papers for academic journals.
|
