| Project/Area Number |
15590295
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Human pathology
|
|---|
| Research Institution | Tohoku University |
|---|
Principal Investigator |
FURUKAWA Toru Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (30282122)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
|
|---|
| Keywords | DUSP6 / MKP-3 / MAPK / pancreatic cancer / microarray / molecular targeting / PanIN / IPMN / hypermethylation / gene therapy / 膵臓がん / マイクロアレイ / 遺伝子発現 / アポトーシス / アデノウィルス |
|---|
| Research Abstract |
To elucidate roles of DUSP6/MKP-3 in development and progression of pancreatic cancer, following investigations were carried out in this research.
1.Expressional profiling of pancreatic cancer cells exogenously overexpressing DUSP6 by using microarray containing 20K genes uncovered 81 upregulated genes and 78 downregulated genes. The upregulated genes comprised five groups of genes (eight in transport seven in receptor activity, six in cell proliferation, four in regulation of transcription, and four in signal transduction) as well as 34 genes with other functions and 18 with unknown function. The downregulated genes comprised three groups of genes (17 in cell cycle and mitosis, seven in DNA replication, and five in receptor signaling pathway) as well as 28 genes with other functions and 21 with unknown function.
2.Analysis of proteins pertaining to apoptosis in cells exogenously overexpressing DUSPG uncovered alterations of BH3-domain proteins and modification of Caspases.
3.Experimental
… More
in vivo gene therapy employing DUSPG by means of injection of the adenovirus vector harboring DUSP6 into inoculated tumors of human pancreatic cancer cells in nude mice revealed remarkable reductions of volumes of several tumors but no statistically significant difference in efficacy overall.
4.Analysis of candidate gene-expression controlling regions of DUSP6 uncovered hypermethylation of CpG islands in intron 1 of DUSP6 in DUSP6-abrogated cancer cells and primary cancer tissues, which was significantly associated with the poorly differentiated phenotype of the latter. Histon modification was found to play an important role in the abrogation as well.
5.Abrogation of DUSPG in precursor lesions in pancreatic tissues with invasive ductal carcinoma or intraductal papillary-mucinous neoplasm (IPMN) was investigated. DUSP6 was fairly expressed in pancreatic intraepithelial neoplasia but lost in invasive carcinoma, indicating strong association of the abrogation with invasive phenotype. A small fraction of IPMN revealed the abrogation, suggesting its association with initiation of IPMN. Less
|
