2006 Fiscal Year Final Research Report Summary
Alterations of DNA methyltransferases during multistage human carcinogenesis
| Project/Area Number |
15390120
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East |
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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)
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| Co-Investigator(Kenkyū-buntansha) |
MAESHIMA Akiko National Cancer Center Hospital, Diagnostic Pathology Division, Staff Scientist (90342906)
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| Project Period (FY) |
2003 – 2006
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| Keywords | DNA methylation / DNA methyltransferase / DNMT1 / DNMT3b / CpG island methylator phenotype / Chromosomal instability / Precancerous condition / Multistage carcinogenesis |
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| 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
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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
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Research Products
(35 results)
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[Journal Article] Increased expression of DNA methyltransferase 1 (DNMT1) protein in uterine cervix squamous cell carcinoma and its precursor lesion.2007
Author(s)
Sawada, M., Kanai, Y., Arai, E., Ushijima, S., Ojima, H., and Hirohashi, S.
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Journal Title
Cancer Lett 251
Pages: 211-219
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Regional DNA hypermethylation and DNA methyltransferase (DNMT) 1 protein overexpression in both renal tumors and corresponding nontumorous renal tissues.2006
Author(s)
Arai, E., Kanai, Y., Ushijima, S., Fujimoto, H., Mukai, K., and Hirohashi, S.
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Journal Title
Int J Cancer 119
Pages: 288-296
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] DNA methylation of multiple tumor-related genes in association with overexpression of DNA methyltransferase 1 (DNMT1) during multistage carcinogenesis of the pancreas.2006
Author(s)
Peng, D.F., Kanai, Y., Sawada, M., Ushijima, S., Hiraoka, N., Kitazawa, S., and Hirohashi, S.
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Journal Title
Carcinogenesis 27
Pages: 1160-1168
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Promoter hypermethylation of the potential tumor suppressor DAL-1 /4. 1B gene in renal clear cell carcinoma. I2006
Author(s)
Yamada, D., Kikuchi, S., Williams, Y.N., Sakurai-Yageta, M., Masuda, M., Maruyama, T., Tomita, K., Gutmann, D.H., Kakizoe, T., Kitamura, T., Kanai, Y., and Murakami, Y.
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Journal Title
Int J Cancer 118
Pages: 916-923
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Epigenetic instability and chromosomal instability in hepatocellular carcinoma.2006
Author(s)
Katoh, H., Shibata, T., Kokubu, A., Ojima, H., Fukayama, M., Kanai, Y., and Hirohashi, S.
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Journal Title
Am J Pathol 168
Pages: 1375-1384
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] DNA hypomethylation on pericentromeric satellite regions significantly correlates with loss of heterozygosity on chromosome 9 in urothelial carcinomas.2005
Author(s)
Nakagawa, T., Kanai, Y., Ushijima, S., Kitamura, T., Kakizoe, T., and Hirohashi, S.
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Journal Title
J Urol 173
Pages: 243-246
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] DNA hypermethylation on multiple CpG islands associated with increased DNA methyltransferase DNMT1 protein expression duiring multistage urothelial carcinogenesis.2005
Author(s)
Nakagawa, T., Kanai, Y., Ushijima, S., Kitamura, T., Kakizoe, T., Hirohashi, S.
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Journal Title
J Urol 173
Pages: 1767-1771
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased DNA methyltransferase 1 (DNMT1) protein expression in precancerous conditions and ductal carcinomas of the pancreas.2005
Author(s)
Peng, D.F., Kanai, Y., Sawada, M., Ushijima, S., Hiraoka, N., Kosuge, T., and Hirohashi, S.
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Journal Title
Cancer Sci 96
Pages: 403-408
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Loss of blood group A antigen expression in bladder cancer caused by allelic loss and/or methylation of the ABO gene.2005
Author(s)
Chihara, Y., Sugano, K., Kobayashi, A., Kanai, Y., Yamamoto, H., Nakazono, M., Fujimoto, H., Kakizoe, T., Fujimoto, K., Hirohashi, S., and Hirao, Y.
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Journal Title
Lab Invest 85
Pages: 895-907
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased DNA methyltransferase 1(DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers.2004
Author(s)
Etoh, T., Kanai, Y., Ushijima, S., Nakagawa, T., Nakanishi, Y., Sasako, M., Kitano, S., and Hirohashi, S.
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Journal Title
Am J Pathol 164
Pages: 689-699
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas.2003
Author(s)
Saito, Y., Kanai, Y., Nakagawa, T., Sakamoto, M., Saito, H., Ishii, H., and Hirohashi, S.
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Journal Title
Int J Cancer 105
Pages: 527-532
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased DNA methyltransferase 1 protein expression in human transitional cell carcinoma of the bladder.2003
Author(s)
Nakagawa, T., Kanai, Y., Saito, Y., Kitamura, T., Kakizoe, T., and Hirohashi, S.
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Journal Title
J Urol 170
Pages: 2463-2466
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Hypermethylation of an E-cadherin (CDH1) promoter region in high grade transitional cell carcinoma of the bladder comprising carcinoma in situ.2003
Author(s)
Horikawa, Y., Sugano, K., Shigyo, M., Yamamoto, H., Nakazono, M., Fujimoto, H., Kanai, Y., Hirohashi, S., Kakizoe, T., Habuchi, T., and Kato, T.
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Journal Title
J Urol 169
Pages: 1541-1545
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Connective Tissue Growth Factor is a putative conditional tumor-suppressor gene frequently inactivated by promoter hypermethylation in ovarian cancer.
Author(s)
Kikuchi, R., Tsuda, H., Kanai, Y., Kasamatsu, T., Sengoku, K., Hirohashi, S., Inazawa, J., and Imoto, I.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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