The role of hypermethylated homeobox gene IRX4 in pancreatic tumorigenesis in
Project/Area Number |
17K15661
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Research Category |
Grant-in-Aid for Young Scientists (B)
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Allocation Type | Multi-year Fund |
Research Field |
Experimental pathology
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Research Institution | Tohoku University |
Principal Investigator |
Gu Zhaodi 東北大学, 医学系研究科, 非常勤講師 (40451520)
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Project Period (FY) |
2017-04-01 – 2019-03-31
|
Project Status |
Completed (Fiscal Year 2018)
|
Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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Keywords | DNAメチル化 / 膵癌 / IRX4 / 腫瘍 / 癌 / ゲノム / 遺伝子 / 発現制御 / アポトーシス / 病理学 |
Outline of Final Research Achievements |
Epigenetic gene silencing by aberrant DNA methylation is one of the important mechanisms leading to the loss of key cellular pathways in tumorigenesis. In order to clarify the significance of aberrant promoter hypermethylation of IRX4 (Iroquois homeobox 4) in pancreatic cancer, we have constructed a tetracycline-inducible IRX4 expressing system using pancreatic cancer cell lines PK-1 and PK-9. IRX4 induction significantly suppressed cell growth and caused apoptosis in PK-1 and PK-9. Because IRX4 is a sequence-specific transcription factor, we tried to analyze IRX4 downstream events by performing microarray analyses using IRX4 inducible PK-1 and PK-9 cells with or without tetracycline. We found that IRX4 induction upregulated several genes that had tumor suppressive functions such as CRYAB, CD69, and IL32. These results suggest that DNA methylation-mediated silencing of IRX4 may contribute to pancreatic tumorigenesis through aberrant transcriptional regulation of cancer-related genes.
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Academic Significance and Societal Importance of the Research Achievements |
エピジェネティックな異常が腫瘍形成に重要な役割を果たすにも関わらず、癌細胞中のDNAメチル化異常は数多く、その中から真のドライバー異常を見出すのは難しい。膵癌形成に重要な役割を果たすDNAメチル化異常を見出すため、DNAメチル化阻害剤、MeTA法の2つの方法で共通にIRX4が同定された。IRX4の遺伝子座5p15.33は、これまで報告されてきた膵癌感受性遺伝子座に一致する。本研究によりIRX4の膵癌における高度メチル化、低発現、IRX4発現の膵癌細胞に与える影響、その原因となるIRX4下流遺伝子群が明らかになった。これらの知見は、膵癌の診断、治療戦略を考える上で、貴重な情報となる可能性が高い。
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Report
(3 results)
Research Products
(2 results)