2021 Fiscal Year Final Research Report
Elucidation of ubiquitin-independent MYCN degradation mechanism mediated by AZ2 in neuroblastoma tumors
Project/Area Number |
19K08283
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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Research Institution | Jikei University School of Medicine |
Principal Investigator |
MURAI NORIYUKI 東京慈恵会医科大学, 医学部, 講師 (60300927)
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Project Period (FY) |
2019-04-01 – 2022-03-31
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Keywords | 神経芽腫 / MYCN / アンチザイム / ユビキチン非依存的分解 / プロテアソーム / がん細胞増殖抑制 |
Outline of Final Research Achievements |
Although neuroblastoma is a rare cancer, about 60% of patients become metastases and the 5-year survival rate is 40%, which is a disease with a poor prognosis. In neuroblastoma, the protooncogene product MYCN is known as a poor prognosis factor. In this study, we found a novel pathway of MYCN degradation mediated by the antizyme 2 (AZ2) protein. We performed knockdown of AZ2 in neuroblastoma cell lines using siRNA and revealed that knockdown of AZ2 causes stabilization of MYCN and increased cell proliferation. In addition, transplantation of AZ2 knockdown cells into mice caused increased tumorigenesis. Furthermore, gene expression analysis and metabolic analysis using AZ2 knockdown cells revealed that the expression of AZ2 suppresses MYCN level, and resulted in decrease of the expression of MYCN target genes, which cause the suppression of cancer cell growth.
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Free Research Field |
生化学、分子生物学
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Academic Significance and Societal Importance of the Research Achievements |
アンチザイム2(AZ2)タンパク質が、神経芽腫の最も強力なリスクファクターであるがん原遺伝子産物MYCNをユビキチン非依存的に分解促進する新規経路を発見しその詳細について解析した。神経芽腫の細胞のAZ2発現を抑えると(ノックダウン)、MYCNが増加し細胞増殖が亢進すること、AZ2をノックダウンしたがん細胞をマウスに移植すると、ノックダウンされていない細胞に比べて明らかに腫瘍形成が増大したことから、AZ2がMYCNを分解促進することによってがん細胞の増殖を抑制できる可能性を見いだした。このことを利用して、神経芽腫においてMYCNをターゲットとした新規分子標的薬開発への展開が期待できる。
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