2006 Fiscal Year Final Research Report Summary
Elucidation, of the interacting mechanism between epigenetic and genetic alterations in gastrointestinal cancers and of the possible application to the clinic
| Project/Area Number |
17390368
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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 |
Digestive surgery
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| Research Institution | Okayama University |
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Principal Investigator |
TANAKA Noriaki Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sdences, Professor, 大学院医歯薬学総合研究科, 教授 (10127566)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUBARA Nagahide Okayama University Medical and Dental Hospital, Assistant Professor, 医学部・歯学部附属病院, 助手 (70314672)
SHIMIZU Kenji Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院医歯薬学総合研究科, 教授 (10037286)
KAMBARA Takeshi Okayama University, Medical School, Visiting Scientist, 医学部, 客員研究員 (60379724)
HAYATSU Hikoya Shujitsu University, School of Pharmacy, Professor, 薬学部, 教授 (10012593)
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| Project Period (FY) |
2005 – 2006
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| Keywords | gastroenterological cancer / carcinogenesis / genetic alteration / epigenetic alteration / colorectal cancer / gastric cancer / esophageal cancer / microsatellite instability |
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| Research Abstract |
We have been studied molecular mechanisms of gastrointestinal carcinogenesis and 'cancer progression. We have been identified several genes whose mutation has a important role in carcinogenesis, including E2F-4 in colorectal and gastric cancer and ING1 in esophageal squamous cell cancer. Recently not only genetic, including mutations and deletions, but also epigenetic alterations are involved in many types of carcinogenesis. The most typical epigenetic alteration is the promoter hypermethylation, which causes the silencing of the gene. DNA methylation occurs preferentially within dense clusters of CpG sites know as CpG islands. Therefore reference is made to a CpG island methylator phenotype (CIMP). Most of our recent work was focused on this promoter methylation of multiple genes in gastrointestinal cancers, and we made tremendous, progress in this' field. We found that the important DNA repair gene MGMT (06-methylguanine DNA methyltransferase) is controlled of its expression by promo
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ter methylation, and the level of methylation is strongly related to the prognosis and chemoresistance of colorectal cancers (Clinical Cancer Research). Furthermore, we classified colorectal cancer by mutational status of KRAS and BRAF, and showed close correlation to the methylation status of the multiple promoter methylation in colorectal cancer (Journal of Clinical Oncology). More recently, we investigated the overall relationship between activation of RAS-RAF signaling pathway and global hypermethylation in a large panel of methylation markers that included both CIMP-related and unrelated loci. In addition, we found that aberrant DNA methylation is only a disease of older individuals with MSI-H but in associated with a subset of Lynch syndrome. Herein, we found that methylation of various epigenetic markers is not a random phenomenon but is clearly segregated with both KRAS and/or BRAF mutations. Thus, overall activation of RAS-RAF pathway associates with aberrant DNA methylation in both sporadic and hereditary colon cancers. We also investigate microRNA as a possible epigenetic role in gastrointestinal carcinogenesis. Less
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Research Products
(13 results)
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[Journal Article] No duplicate KRAS mutation is identified on the same allele of gastric or colorectal cancer cells with multiple KRAS mutations.2007
Author(s)
Kimura, K., Nagasaka, T., Sasamoto, H., Notohara, K., Takeda, M., Komnami, K., Ishii, T., Tanaka, N., Matsubara, N.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Oesophageal squamous cell cancer may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa.2007
Author(s)
Ishii, T., Murakami, J., Notohara, K., Cullings, H.M., Sasamoto, H., Kambara, T., Shirakawa, Y., Naomoto, Y., Ouchida, M., Shimizu, K., Tanaka, N., Jass, J.R., Matsubara, N.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis.2006
Author(s)
Ozaki, K., Nagasaka, T., Notohara, K., Kambara, T., Takeda, M., Sasamoto, H., Jass, J.R., Tanaka, N., Matsubara, N.
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Journal Title
Int. J. Cancer 119 (11)
Pages: 2513-2519
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Role of 06-methylguanine-DNA methyltransferase and effect of 06-benzylguanine on the anti-tumor activity of cis-Diaminedichloroplatinum(II) in oral cancer cell lines.2005
Author(s)
Yu Maki, Jun Murakami, Jun-ichi Asaumi, Hidetsugu Tsujigiwa, Hitoshi Nagatsuka, Susumu Kokeguchi, Kazuhiro Fukui, Noriko Kawai, Yoshinobu Yanagil, Masahiro Kuroda, Noriaki Tanaka, Nagahide Matsubara, Kanji Kishil
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Journal Title
Oral Oncol. 41
Pages: 984-993
Description
「研究成果報告書概要(欧文)」より
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