| Project/Area Number |
15390120
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Human pathology
|
|---|
| Research Institution | National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East |
|---|
Principal Investigator |
KANAI Yae National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East, National Cancer Center Reaearch Institute, Pathology Division, Chief (00260315)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
MAESHIMA Akiko National Cancer Center Hospital, Diagnostic Pathology Division, Staff Scientist (90342906)
|
|---|
| Project Period (FY) |
2003 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2006: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥6,300,000 (Direct Cost: ¥6,300,000)
|
|---|
| Keywords | DNA methylation / DNA methyltransferase / DNMT1 / DNMT3b / CpG island methylator phenotype / Chromosomal instability / Precancerous condition / Multistage carcinogenesis / CpGアイランド / 慢性膵炎 / PanIN / 膵管がん / Pan IN / 浸潤性膵管がん / 腎細胞がん / 傍セントロメアサテライト領域 / 膀胱がん / 移行上皮がん / 前がん段階 / EBウイルス / hMLH1 / E-カドヘリン |
|---|
| Research Abstract |
The expression level of DNMT1 was higher in liver tissues showing chronic hepatitis or cirrhosis than in normal liver tissues, and was even higher in hepatoceellular carcinomas (HCCs). DNMT1 overexpression in HCCs is correlated with poorer tumor differentiation and portal vein involvement. DNMT1 overexpression was detected in peripheral pancreatic ductal epithelia with an inflammatory background and pancreatic intraepithelial neoplasias. DNMT1 overexpression is associated with aggressiveness of pancreatic cancers and accumulation of methylated tumor-related genes. Patients with HCCs and pancreatic cancers showing DNMT1 overexpression have a poorer prognosis. DNMT1 overexpression in stomach cancers is correlated with CpG island methylator phenotype and Epstein-Barr virus infection. DNMT1 overexpression was also found in cervical intraepithelial neoplasias closely associated with human papillomavirus infection. In non-cancerous urothelia showing no remarkable histological findings which
… More
can be exposed to carcinogens in the urine, DNMT1 overexpression preceded increased cell proliferative activity. DNMT1 overexpression may participate in multistage carcinogenesis, from precancerous conditions to malignant progression, through induction of regional DNA hypermethylation.
DNA hypomethylation of pericentromeric satellite regions was detected in liver tissues showing chronic hepatitis or cirrhosis and HCCs. DNMT3b is specifically required for DNA methylation of such regions. Normal liver tissues show only a trace level of DNMT3b4, a splice variant not showing DNMT activity. The expression level of DNMT3b4 in liver tissues showing chronic hepatitis or cirrhosis and HCCs was correlated with the degree of DNA hypomethylation of pericentromeric satellite regions. The ratio of DNMT3b4 mRNA to DNMT3b3, the major active variant in normal liver tissues, was also correlated with the degree of DNA hypomethylation. DNMT3b4 may compete with DNMT3b3 for targeting to pericentromeric satellite regions. DNA demethylation on satellite 2 was observed in DNMT3b4 transfectants. DNMT3b4 overexpression may lead to chromosomal instability through DNA hypomethylation of pericentromeric satellite regions during hepatocarcinogenesis. Less
|
