2003 Fiscal Year Final Research Report Summary
Application of DNA methylation analysis to tretment of gastrointestinal cancer.
| Project/Area Number |
14370188
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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 |
Gastroenterology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
YOSHIDA Yukinari Sapporo Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (60311411)
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| Co-Investigator(Kenkyū-buntansha) |
ITOH Fumio Sapporo Medical University, School of Medicine, Professor, 医学部, 教授 (90223180)
YAMAMOTO Hiroyuki Sapporo Medical University, School of Medicine, Instructor, 医学部, 助手 (40332910)
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| Project Period (FY) |
2002 – 2003
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| Keywords | DNA methylation / CIMP / gastrointestinal cancer / methylation inhibitor / histone acetylation / anti-cancer drug sensitivity / taxane / CHFR |
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| Research Abstract |
CpG island methylator phenotype(CIMP) has been found to be implicated in the development of various malignancies. We have previously reporeted that a subset of gastric and colorectal cancers domonstrated CIMP. CIMP positive gastrointestinal tumors present a potentially distinct genetic pathway in which p53 or K-ras mutations are rare. In the other hand, hypermethylation of p16 or MLH1 gene promotor, leading to gene silencing, have been frequently shown.
In the present study, we examined the methylation status of CHFR, which delays chromosome condensation during prophase in response to mitotic stress caused by microtubule poisoning, in gastrointestinal cancers. CHFR expression was silenced by DNA methylation of the gene promotor in 40% of both primary gastric and colorectal cancers. In addition, histones H3 and H4 were found to be deacetylated in cell lines showing aberrant methylation, indicating a role for histone deacetylation in the methylation-dependent gene silencing. Furthermore, the absence of CHFR is associated with sensitivity of cells to mitotic stress caused by taxanes, microtubule inhibitors, and restoration of CHFR expression by 5-aza-2'-deoxycytidine restored the checkpoint. By affecting mitotic checkpopint function, CHFR inactivation likely plays a role in tumorigenesis in gastrointestinal cancers. Moreover, the abberant methylation of CHFR appears to be a good molecular marker with which to predict the sensitivity of gastrointestinal cancers to microtubule inhibitors.
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