| Project/Area Number |
15390535
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatric surgery
|
|---|
| Research Institution | Chiba Cancer Center Research Institute |
|---|
Principal Investigator |
NAKAGAWARA Akira Chiba Cancer Center Research Institute, Director, 研究局, 局長 (50117181)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OZAKI Toshinori Chiba Cancer Center Research Institute, Division of Biochemistry, Researcher, 生化学研究部, 上席研究員 (40260252)
ICHIKAWA Miki (OHIRA Miki) Chiba Cancer Center Research Institute, Division of Biochemistry, Researcher, 生化学研究部, 研究員 (20311384)
|
|---|
| Project Period (FY) |
2003 – 2004
|
| Project Status |
Completed (Fiscal Year 2004)
|
| Budget Amount *help |
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2004: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 2003: ¥7,400,000 (Direct Cost: ¥7,400,000)
|
|---|
| Keywords | p53 / p73 / Mdm2 / multi-drug resistance / BMP2 / neuroblastoma / cDNA microarray / p63 / MYCN / ΔNp73 / シスプラチン耐性 |
|---|
| Research Abstract |
We have examined the role of p53 family genes in the genesis and acquisition of multi-drug resistance in human neuroblastoma. The results we obtained are as follows. (1)Mutation of the p53 gene was very rare in primary neuroblastomas obtained at initial surgery. However, it was induced in recurrent tumors as well as in many neuroblastoma cell lines. Among 30 neuroblastoma cell lines, we found 6 loss of function mutations in the p53 gene by yeast functional assay and DNA sequencing. Furthermore, we found that high levels of p53 mRNA expression were significantly associated with poor prognosis of neuroblastoma by using our in-house cDNA microarray which carried 5,300 cDNAs obtained from primary neuroblastoma cDNA libraries we generated. In addition, it is already known that p53 is often localized in cellular cytoplasm in advanced stages neuroblastomas. These suggest that p53 may function in primary neuroblastomas to regulate the tumor growth and apoptosis. (2)We searched for the role of p53 family genes in retinoic acid-induced apoptosis of neuroblastoma cells. However, the levels of p53 family molecules were too low to be detected. Only p73 protein was induced at the protein level. (3)In the panel of human cancer cell lines including neuroblastoma, the levels of p73 and p63 expression were high in the lines with resistance to cisplatin. Our further analysis revealed that Mdm2 expression was high in those cisplatin-resistant cell lines, that in turn induced degradation of p53 protein, leading to acquiring the resistance. Currently, we are further searching for the precise mechanism to develop new therapeutic strategies against aggressive neuroblastomas.
|
